Isoxazoline derivative and herbicide comprising the same as active ingredient

ABSTRACT

An isoxazoline derivative represented by the following general formula [I]: 
                         
wherein R 1  and R 2  may be the same or different and are each an alkyl group;
         R 3 , R 4 , R 5  and R 6  are each a hydrogen atom;   Y is an optionally substituted 5- to 6-membered aromatic heterocyclic group or fused aromatic heterocyclic group having a hetero atom selected from a nitrogen atom, a oxygen atom and a sulfur atom; and   n is an integer: of 0 to 2.       
     The isoxazoline derivative has an excellent herbicidal effect and an excellent selectivity between crop and weed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase Application (35 USC 371) ofPCT/JP02/01015 and claims priority of Japanese Application No.2001-031784 filed Feb. 8, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel isoxazoline derivative and aherbicide containing the isoxazoline derivative as the activeingredient.

2. Description of the Prior Art

The herbicidal activity of isoxazoline derivatives are reported in, forexample, JP-A-8-22558, JP-A-9-328477 and JP-A-9-328483. The compound ofthe present invention described in detail later, however, is notdescribed in these literatures.

Herbicides applied to useful crops are desired to (a) be applicable tosoil or foliage, (b) show a sufficient herbicidal effect at a lowingredient amount, and (c) show a high selectivity between crop andweed. In these respects, the compounds described in the aboveliteratures are not fully satisfactory.

SUMMARY OF THE INVENTION

In view of the above situation, the present inventors made a study onthe herbicidal effect and selectivity between crop and weed of variouscompounds. As a result, the present inventors found out that a novelisoxazoline derivative has an excellent herbicidal effect and anexcellent selectivity between crop and weed. The above finding has ledto the completion of the present invention.

The present invention provides the followings.

-   (1) An isoxazoline derivative represented by the following general    formula [I] or a pharmaceutically acceptable salt thereof:

wherein R¹ and R² may be the same or different and are each a hydrogenatom, a C1 to C10 alkyl group, a C3 to C8 cycloalkyl group or a C3 to C8cycloalkyl C1 to C3 alkyl group, or R¹ and R² may be bonded to eachother to form a C3 to C7 spiro ring together with the carbon atoms towhich they bond;

R³ and R⁴ may be the same or different and are each a hydrogen atom, aC1 to C10 alkyl group or a C3 to C8 cycloalkyl group; or R³ and R⁴ maybe bonded to each other to form a C3 to C7 spiro ring together with thecarbon atoms to which they bond; or R¹, R², R³ and R⁴ may form a 5- to8-membered ring together with the carbon atoms to which they bond;

R⁵ and R⁶ may be the same or different and are each a hydrogen atom or aC1 to C10 alkyl group;

Y is a 5- to 6-membered aromatic heterocyclic group or condensedaromatic heterocyclic group having one or more hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom; the heterocyclicgroup may be substituted with 0 to 6 same or different groups selectedfrom the following substituent group α; when the heterocyclic group issubstituted at the two adjacent positions with two alkyl groups, twoalkoxy groups, an alkyl group and an alkoxy group, an alkyl group and analkylthio group, an alkyl group and an alkylsulfonyl group, an alkylgroup and a monoalkylamino group, or an alkyl group and a dialkylaminogroup, all selected from the substituent group α, the two groups mayform, together with the atoms to which they bond, a 5- to 8-memberedring which may be substituted with 1 to 4 halogen atoms; the hetero atomof the heterocyclic group, when it is a nitrogen atom, may be oxidizedto become N-oxide;

n is an integer of 0 to 2.

[Substituent Group α]

Hydroxyl group; thiol group; halogen atoms; C1 to C10 alkyl groups; C1to C10 alkyl groups each mono-substituted with a group selected from thefollowing substituent group β, C1 to C4 haloalkyl groups; C3 to C8cycloalkyl groups; C1 to C10 alkoxy groups; C1 to C10 alkoxy groups eachmono-substituted with a group selected from the following substituentgroup γ; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3to C8 cycloalkyl C1 to C3 alkyloxy groups; C1 to C10 alkylthio groups;C1 to C10 alkylthio groups each mono-substituted with a group selectedfrom the substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6alkenyl groups; C2 to C6 alkenyloxy groups; C2 to C6 alkynyl groups; C2to C6 alkynyloxy groups; C1 to C10 alkylsulfinyl groups; C1 to C10alkylsulfinyl groups each mono-substituted with a group selected fromthe substituent group γ; C1 to C10 alkylsulfonyl groups; C1 to C10alkylsulfonyl groups each mono-substituted with a group selected fromthe substituent group γ; C1 to C4 haloalkylsulfinyl groups; C1 to C10alkylsulfonyloxy groups each mono-substituted with a group selected fromthe substituent group γ; C1 to C4 haloalkylsulfonyl groups; C1 to C10alkylsulfonyloxy groups; C1 to C4 haloalkylsulfonyloxy groups;optionally substituted phenyl group; optionally substituted phenoxygroup; optionally substituted phenylthio group; optionally substitutedaromatic heterocyclic groups; optionally substituted aromaticheterocyclic oxy groups; optionally substituted aromatic heterocyclicthio groups; optionally substituted phenylsulfinyl groups; optionallysubstituted phenylsulfonyl groups; optionally substituted aromaticheterocyclic sulfonyl groups; optionally substituted phenylsulfonyloxygroups; acyl groups; C1 to C4 haloalkylcarbonyl groups; optionallysubstituted benzylcarbonyl group; optionally substituted benzoyl group;carboxyl group; C1 to C10 alkoxycarbonyl groups; optionally substitutedbenzyloxycarbonyl group; optionally substituted phenoxycarbonyl group;cyano group; carbamoyl group (its nitrogen atom may be substituted withsame or different groups selected from C1 to C10 alkyl groups andoptionally substituted phenyl group); C1 to C6 acyloxy groups; C1 to C4haloalkylcarbonyloxy groups; optionally substituted benzylcarbonyloxygroup; optionally substituted benzoyloxy group; nitro group; and aminogroup (its nitrogen atom may be substituted with same or different:groups selected from C1 to C10 alkyl groups, optionally substitutedphenyl group, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups,optionally substituted benzylcarbonyl group, optionally substitutedbenzoyl group, C1 to C10 alkylsulfonyl group, C1 to C4 haloalkylsulfonylgroups, optionally substituted benzylsulfonyl group, and optionallysubstituted phenylsulfonyl group).

[Substituent Group β]

Hydroxyl group; C3 to C8 cycloalkyl groups which may be substituted withhalogen atom or alky group); C1 to C10 alkoxy groups; C1 to C10alkylthio groups; C1 to C10 alkylsulfonyl groups; C1 to C10alkoxycarbonyl groups; C2to C6 haloalkenyl groups; amino group (itsnitrogen atom may be substituted with same or different groups selectedfrom C1 to C10 alkyl groups, C1 to C6 acyl groups; C1 to C4haloalkylcarbonyl groups, C1 to C10 alkylsulfonyl groups and C1 to C4haloalkylsulfonyl groups); carbamoyl group (its nitrogen atom may besubstituted with same or different C1 to C10 alkyl groups); C1 to C6acyl groups; C1 to C4 haloalkylcarbonyl groups; C1 to C10 alkoxyiminogroups; cyano group; optionally substituted phenyl group; and optionallysubstituted phenoxy group.

[Substituent Group γ]

C1 to C10 alkoxycarbonyl groups; optionally substituted phenyl group;optionally substituted aromatic heterocyclic groups; cyano group; andcarbamoyl group (its nitrogen atom may be substituted with same ordifferent C1 to C10 alkyl groups).

-   (2) An isoxazoline derivative-according to (1), wherein the    substituent group α on the heterocycle which may be substituted with    0 to 6 same or different groups, includes hydroxyl group; halogen    atoms; C1 to C10 alkyl groups; C1 to C10 alkyl groups each    mono-substituted with a group selected from the substituent group β,    C1 to C4 haloalkyl groups; C3 to C8 cycloalkyl groups; C1 to C10    alkoxy groups; C1 to C10 alkoxy groups each mono-substituted with a    group selected from the substituent group γ; C1 to C4 haloalkoxy    groups; C3 to C8 cycloalkyloxy groups; C3 to C8 cycloalkyl C1 to C3    alkyloxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylthio    groups each mono-substituted with a group selected from the    substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6 alkenyl    groups; C2 to C6 alkenyloxy groups; C2 to C6 alkynyl groups; C2 to    C6 alkynyloxy groups; C1 to C10 alkylsulfonyl groups; C1 to C4    haloalkylsulfonyl groups; optionally substituted phenyl group;    optionally substituted phenoxy group; optionally substituted    phenylthio group; optionally substituted aromatic heterocyclic    groups; optionally substituted aromatic heterocyclic oxy groups;    optionally substituted aromatic heterocyclic thio groups; optionally    substituted phenylsulfonyl groups; optionally substituted aromatic    heterocyclic sulfonyl groups; C1 to C6 acyl groups; C1 to C4    haloalkylcarbonyl groups; optionally substituted benzylcarbonyl    group; optionally substituted benzoyl group; carboxyl group; C1 to    C10 alkoxycarbonyl groups; cyano group; carbamoyl group (its    nitrogen atom may be substituted with same or different groups    selected from C1 to C10 alkyl groups and optionally substituted    phenyl group); nitro group; and amino group (its nitrogen atom may    be substituted with same or different groups selected from C1 to C10    alkyl groups, optionally substituted phenyl group, C1 to C6 acyl    groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted    benzylcarbonyl group, optionally substituted benzoyl group, C1 to    C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups,    optionally substituted benzylsulfonyl group, and optionally    substituted phenylsulfonyl group); when the heterocyclic group is    substituted at the two adjacent positions with two alkyl groups, two    alkoxy groups, an alkyl group and an alkoxy group, an alkyl group    and an alkylthio group, an alkyl group and an alkylsulfonyl group,    an alkyl group and a monoalkylamino group, or an alkyl group and a    dialkylamino group, all selected from the substituent group α, the    two groups may form, together with the atoms to which they bond, a    5- to 8-membered ring which may be substituted with 1 to 4 halogen    atoms.-   (3) An isoxazoline derivative according to (2), wherein the    substituent group α on the heterocycle which may be substituted with    0 to 6 same or different groups, includes halogen atoms; C1 to C10    alkyl groups; C1 to C4 haloalkyl groups; C1 to C10 alkoxy C1 to C3    alkyl groups; C3 to C8 cycloalkyl groups which may be substituted    with halogen atom or alkyl group; C1 to C10 alkoxy groups; C1 to C4    haloalkoxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxy groups;    optionally substituted phenoxy group; C1 to C10 alkylthio groups; C1    to C10 alkylsulfonyl groups; acyl groups; C1 to C4 haloalkylcarbonyl    groups; C1 to C10 alkoxycarbonyl groups; cyano group and carbamoyl    group (its nitrogen atom may be substituted with same or different    C1 to C10 alkyl groups).-   (4) An isoxazoline derivative according to any of (1), (2) or (3),    wherein R¹ and R² may be the same or different and are each a methyl    group or an ethyl group; and R³, R⁴, R⁵ and R⁶ are each a hydrogen    atom.-   (5) An isoxazoline derivative according to any of (1), (2), (3)    or (4) wherein Y is a 5- or 6-membered aromatic heterocyclic group    having a hetero atom selected from a nitrogen atom, an oxygen atom    and a sulfur atom.-   (6) An isoxazoline derivative according to (5), wherein Y is a    thienyl group, a pyrazolyl group, an isoxazolyl group, an    isothiazolyl group, a pyridyl group or a pyrimidinyl group.-   (7) An isoxazoline derivative according to (6), wherein Y is a    thiophen-3-yl group, a pyrazol-4-yl group, a pyrazol-5-yl group, an    isoxazol-4-yl group, an isothiazol-4-yl group, a pyridyn-3-yl group    or a pyrimidin-5-yl group.-   (8) An isoxazoline derivative according to (7), wherein Y is a    thiophen-3-yl group and the thiophene ring is substituted with the    substituent group α at the 2- and 4-positions.-   (9) An isoxazoline derivative according to (7), wherein Y is a    pyrazol-4-yl group and the pyrazole ring is substituted at the 3-    and 5-positions with the substituent group α and at the 1-position    with a hydrogen atom, a C1 to C10 alkyl group, a C1 to C10 alkyl    group mono-substituted with a group selected from the substituent    group β, a C1 to C4 haloalkyl group, a C3 to C8 cycloalkyl group, a    C2 to C6 alkenyl group, a C2 to C6 alkynyl group, a C1 to C10    alkylsulfinyl group, a C1 to C10 alkylsulfonyl group, a C1 to C10    alkylsulfonyl group mono-substituted with a group selected from the    substituent group γ, a C1 to C4 haloalkylsulfonyl group, an    optionally substituted phenyl group, an optionally substituted    aromatic heterocyclic group, an optionally substituted    phenylsulfonyl group, an optionally substituted aromatic    heterocyclic sulfonyl group, an acyl group, a C1 to C4    haloalkylcarbonyl group, an optionally substituted benzylcarbonyl    group, an optionally substituted benzoyl group, a C1 to C10    alkoxycarbonyl group, an optionally substituted benzyloxycarbonyl    group, an optionally substituted phenoxycarbonyl group, a carbamoyl    group (its nitrogen atom may be substituted with same or different    groups selected from C1 to C10 alkyl groups and optionally    substituted phenyl group), or an amino group (its nitrogen atom may    be substituted with same or different groups selected from C1 to C10    alkyl groups, optionally substituted phenyl group, acyl groups, C1    to C4 haloalkylcarbonyl groups, optionally substituted    benzylcarbonyl group, optionally substituted benzoyl group, C1 to    C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups,    optionally substituted benzylsulfonyl group and optionally    substituted phenylsulfonyl group).-   (10) An isoxazoline derivative according to (7), wherein Y is a    pyrazol-5-yl group and the pyrazole ring is substituted at the    4-position with the substituent group α and at the 1-position with a    hydrogen atom, a C1 to C10 alkyl group, a C1 to C10 alkyl group    mono-substituted with a group selected from the substituent group β,    a C1 to C4 haloalkyl group, a C3 to C8 cycloalkyl group, a C2 to C6    alkenyl group, a C2 to C6 alkynyl group, a C1 to C10 alkylsulfinyl    group, a C1 to C10 alkylsulfonyl group, a C1 to C10alkylsulfonyl    group mono-substituted with a group selected from the substituent    group γ, a C1 to C4 haloalkylsulfonyl group, an optionally    substituted phenyl group, an optionally substituted aromatic    heterocyclic group, an optionally substituted phenylsulfonyl group,    an optionally substituted aromatic heterocyclic sulfonyl group, an    acyl group, a C1 to C4 haloalkylcarbonyl group, an optionally    substituted benzylcarbonyl group, an optionally substituted benzoyl    group, a C1 to C10 alkoxycarbonyl group, an optionally substituted    benzyloxycarbonyl group, an optionally substituted phenoxycarbonyl    group, a carbamoyl group (its nitrogen atom may be substituted with    same or different groups selected from C1 to C10 alkyl groups and    optionally substituted phenyl group), or an amino group (its    nitrogen atom may be substituted with same or different groups    selected from C1 to C10 alkyl groups, optionally substituted phenyl    group; acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally    substituted benzylcarbonyl group, optionally substituted benzoyl    group, C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl    groups, optionally substituted benzylsulfonyl group and optionally    substituted phenylsulfonyl group).-   (11) An, isoxazoline derivative according to (7), wherein Y is an    isoxazol-4-yl group and the isoxazole ring is substituted with the    substituent group α at the 3- and 5-positions.-   (12) An isoxazoline derivative according to (7), wherein Y is an    isothiazol-4-yl group and the isothiazole ring is substituted with    the substituent group α at the 3- and 5-positions.-   (13) An isoxazoline derivative according to (7), wherein Y is a    pyridin-3-yl group and the pyridine ring is substituted with the    substituent group α at the 2- and 4-positions.-   (14) An isoxazoline derivative according to (7), wherein Y is a    pyrimidin-5-yl group and the pyrimidine ring is substituted with the    substituent group α at the 4- and 6-positions.-   (15) An isoxazoline derivative according to any of (1) to (14),    wherein n is an integer of 2.-   (16) An isoxazoline derivative according to any of (1) to (14),    wherein n is an integer of 1.-   (17) An isoxazoline derivative according to any of (1) to (14),    wherein n is an integer of 0.-   (18) A herbicide containing, as the active ingredient, an    isoxazoline derivative set forth in any of (1) to (17) or a    pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The definitions of the terms used in the present specification are givenbelow.

The expression of “C1 to C10”, etc. indicates that the substituentappearing after the expression has 1 to 10 carbon atoms in the case of“C1 to C10”.

Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atomor an iodine atom.

C1 to C10 alkyl group refers to a straight or branched chain alkyl groupof 1 to 10 carbon atoms unless other wise specified; and there can bementioned, for example, methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, n-pentyl group, isopentyl group, neopentyl group,n-hexyl group, isohexyl group, 3,3-dimethylbutyl group, heptyl group andoctyl group.

C3 to C8 cycloalkyl group refers to a cycloalkyl group of 3 to 8 carbonatoms; and there can be mentioned, for example, cyclopropyl group,cyclobutyl group, cyclopentyl group and cyclohexyl group.

C3 to C8 cycloalkyl C1 to C3 alkyl group (which may be substituted withhalogen atom or alkyl group) refers, unless otherwise specified, to a C1to C3 alkyl group substituted with a C3 to C8 cycloalkyl group which maybe substituted with 1 to 4 same or different halogen atoms or C1 to C3alkyl group; and there can be mentioned, for example, cyclopropylmethylgroup, 1-cyclopropylethyl group, 2-cyclopropylethyl group,1-cyclopropylpropyl group, 2-cyclopropylpropyl group,3-cyclopropylpropyl group, cyclobutylmethyl group, cyclopentylmethylgroup, cyclohexylmethyl group, 2-chlorocyclopropylmethyl group,2,2-dichlorocyclopropylmethyl group, 2-fluorocyclopropylmethyl group,2,2-difluorocyclopropylmethyl group, 2-methylcyclopropylmethyl group,2,2-dimethylcyclopropylmethyl group and 2-methylcyclopropylethyl group.

C3 to C8 cycloalkyl C1 to C3 alkyl group refers to a alkyl group of 1 to3 carbon atoms, substituted with a cycloalkyl group of 3 to 8 carbonatoms; and there can be mentioned, for example, cyclopropylmethyl group,1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropylpropylgroup, 2-cyclopropylpropyl group, 3-cyclopropylpropyl group,cyclobutylmethyl group, cyclopentylmethyl group and cyclohexylmethylgroup.

C1 to C4 haloalkyl group refers, unless otherwise specified, to astraight or branched chain alkyl group of 1 to 4 carbon atoms,substituted with 1 to 9 same or different halogen atoms; and there canbe mentioned, for example, fluoromethyl group, chloromethyl group,bromomethyl group, difluoromethyl group, trifluoromethyl group,2,2-difluoroethyl group, 2,2,2-trifluoroethyl group and pentafluoroethylgroup.

C2 to C6 alkenyl group refers to a straight or branched chain alkenylgroup of 2 to 6 carbon atoms; and there can be mentioned, for example,ethenyl group, 1-propenyl group, 2-propenyl group, isopropenyl group,1-butenyl group, 2-butenyl group, 3-butenyl group and 2-pentenyl group.

C2 to C6 alkynyl group refers to a straight or branched chain alkynylgroup of 2 to 6 carbon atoms; and there can be mentioned, for example,ethynyl group, 2-propynyl group, 1-methyl-2-propynyl group, 2-butynylgroup, 3-butynyl group and 2-methyl-3-butynyl group.

C2 to C6 haloalkenyl group refers, unless otherwise specified, to astraight or branched alkenyl group of 2 to 6 carbon atoms, substitutedwith 1 to 4 same or different halogen atoms; and there can be mentioned,for example, 3-chloro-2-propenyl group and, 2-chloro-2-propneyl group.

C1 to C10 alkoxy group refers to an (alkyl)-O— group wherein the alkylmoiety has the above definition; and there can be mentioned, forexample, methoxy group, ethoxy group, n-propoxy group, isopropoxy group,tert-butoxy group, n-butoxy group, sec-butoxy group and isobutoxy group.

C1 to C4 haloalkoxy group refers to a (haloalkyl)-O— group wherein thehaloalkyl moiety has the above definition; and there can be mentioned,for example, difluoromethoxy group, trifluoromethoxy group,2,2-difluoroethoxy group and 2,2,2-trifluoroethoxy group.

C3 to C8 cycloalkyloxy group refers to a (cycloalkyl)-O— group whereinthe cycloalkyl moiety has the above definition; and there can bementioned, for example, cyclopropyloxy group, cyclobutyloxy group,cyclopentyloxy group and cyclohexyloxy group.

C3 to C8 cycloalkyl C1 to C3 alkyloxy group refers to a(cycloalkylalkyl)-O— group wherein the cycloalkylalkyl moiety has theabove definition; and there can be mentioned, for example,cyclopropylmethoxy group, 1-cyclopropylethoxy group, 2-cyclopropylethoxygroup, 1-cyclopropylpropoxy group, 2-chclopropylpropoxy group,3-cyclopropylpropoxy group, cyclobutylmethoxy group, cyclopentylmethoxygroup and cyclohexylmethoxy group.

C2 to C6 alkenyloxy group and C2 to C6 alkynyloxy group refer,respectively, to an (alkenyl)-O— group and an (alkynyl)-O— group, ineach of which the alkenyl or alkynyl moiety has the above definition;and there can be mentioned, for example, 2-propenyloxy group and2-propynyloxy group.

C1 to C10 alkoxyimino group refers to an (alkoxy)-N═ group wherein thealkoxy moiety has the above definition; and there can be mentioned, forexample, methoxyimino group and ethoxyimino group.

C1 to C10 alkylthio group, C1 to C10 alkylsulfinyl group and C1 to C10alkylsulfonyl group refer, respectively, to an (alkyl)-S— group, an(alkyl)-SO— group and an (alkyl)-SO₂— group, in each of which the alkylmoiety has the above definition; and there can be mentioned, forexample, methylthio group, ethylthio group, n-propylthio group,isopropylthio group, methylsulfinyl, group, methylsulfonyl group,ethylsulfonyl group, n-propylsulfonyl group and isopropylsulfonyl group.

C1 to C10 alkylsulfonyloxy group refers to an (alkylsulfonyl)-O— groupwherein the alkylsulfonyl moiety has the above definition, and there canbe mentioned, for example, methylsulfonyloxy group and ethylsulfonyloxygroup.

C1 to C10 alkoxycarbonyl group refers to an (alkoxy)-CO— group whereinthe alkoxy moiety has the above definition, and there can be mentioned,for, example, methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group and isopropoxycarbonyl group.

C1 to C6 acryl group refers to a straight or branched chain aliphaticacyl group of 1 to 6 carbon atoms, and there can be mentioned, forexample, formyl group, acetyl group, propionyl group, isopropionylgroup, butyryl group and pivaloyl group.

C1 to C10 acyloxy group refers to an (acyl)-O— group wherein the acylmoiety has the above definition; and there can be mentioned, forexample, acetoxy group, propionyloxy group, ispropionyloxy group andpivalolyoxy group.

C1 to C4 haloalkylcarbonyl group, C1 to C4 haloalkylthio group and C1 toC4 haloalkylsulfonyl group refers, respectively, to a (haloalkyl)-CO—group, a (haloalkyl)-S— group and a (haloalkyl)-SO₂— group, in each ofwhich the haloalkyl moiety has the above definition; and there can bementioned, for example, chloroacetyl group, trifluoroacetyl group,pentafluoropropyl group, difluoromethylthio group, trifluoromethylthiogroup, chloromethylsulfonyl group, difluoromethylsulfonyl group andtrifluoromethylsulfonyl group.

C1 to C4 haloalkylcarbonyloxy group and C1 to C4 haloalkylsulfonyloxygroup refer, respectively, to a (haloalkylcarbonyl)-O— group and a(haloalkylsulfonyl)-O— group, in each of which the haloalkylcarbonylmoiety or the haloalkylsulfonyl moiety has the above definition; andthere can be mentioned, for example, chloroacetyloxy group,trifluoroacetyloxy group, chloromethylsulfonyloxy group andtrifluoromehtylsulfonyloxy group.

“Optionally substituted” in (optionally substituted) phenyl group,(optionally substituted) aromatic heterocyclic group, (optionallysubstituted) phenoxy group, (optionally substituted aromaticheterocyclic oxy group, (optionally substituted) phenylthio group,(optionally substituted) aromatic heterocyclic thio group, (optionallysubstituted) phenylsulfonyl group, (optionally substituted)phenylsulfonyloxi group, (optionally substituted) aromatic heterocyclicsulfonyl group, (optionally substituted) benzylcarbonyl group,(optionally substituted) benzylcarbonyloxy group, (optionallysubstituted) benzylsulfonyl group, (optionally substituted) benzoylgroup, (optionally substituted) benzoyloxy group, (optionallysubstituted) benzyloxycarbonyl group and (optionally substituted)phenoxycarbonyl group, refers to being optionally substituted with, forexample, halogen atom, C1 to C10 alkyl group, C1 to C4haloalkyl group,C1 to C10 alkoxyalkyl group, C1 to C10 alkoxy group, C1 to C10 alkylthiogroup, C1 to C10 alkylsulfonyl group, acyl group, C1 to C10alkoxycarbonyl group, cyano group, carbamoyl group (its nitrogen atommay be substituted with same or different C1 to C10 alkyl groups) nitrogroup or amino group (its nitrogen atom may be substituted with same ordifferent groups selected from C1 to C10 alkyl groups, C1 to C6 acylgroups, C1 to C4 haloalkylcarbonyl groups, C1 to C10 alkylsulfonylgroups and C1 to C4 haloalkylsulfonyl groups).

5- to 6-membered aromatic heterocyclic group having a hetero atomselected from a nitrogen atom, an oxygen atom and a sulfur atomincludes, for example, furyl group, thienyl group, pyrrolyl group,pyrazolyl group, isoxazolyl group, isothiazolyl group, oxazolyl group,thiazolyl group, imidazolyl group, pyridyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, triazinyl group, triazolyl group,oxadiazolyl group and thiadiazolyl group, each having 1 to 3 heteroatoms.

Fused aromatic heterocyclic group refers to a group having 1 to 3 heteroatoms randomly selected from nitrogen atom, oxygen atom and sulfur atom;and there can be mentioned, for example, benzofuryl group, benzothienylgroup, indolyl group, benzoxazolyl group, benzothiazolyl group,benzimidazolyl group, benzisoxazolyl group, benzisothiazolyl group,indazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group,quinoxalinyl group, quinazolinyl group, cinnolinyl group andbenzotriazolyl group.

Aromatic heterocycle in (optionally substituted) aromatic heterocyclicgroup, (optionally, substituted) aromatic heterocyclic oxy group,(optionally substituted) aromatic heterocyclic thio group and(optionally substituted) aromatic heterocyclic sulfonyl group, refers toa 5- to 6-membered group having 1 to 3 hetero atoms randomly selectedfrom nitrogen atom, oxygen atom and sulfur atom; and there can bementioned, for example, furyl group, thienyl group, pyrrolyl group,pyrazolyl group, isoxazolyl group, isothiazolyl group, oxazolyl group,thiazolyl group, imidazolyl group, pyridyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, triazinyl group, triazolyl group,oxadiazolyl group and thiadiazolyl group.

Pharmaceutically acceptable salt is a salt of a compound of the generalformula [I] having, in the structure, hydroxyl group, carboxyl group,amino group or the like, with a metal or an organic base or with amineral acid or an organic acid. As the metal, there can be mentionedalkali metals such as sodium, potassium and the like; and alkaline earthmetals such as magnesium, calcium and the like. As the organic base,there can be mentioned triethylamine, diisopropylamine, etc. As themineral acids, there can be mentioned hydrochloric acid, sulfuric acid,etc. As the organic acid, there can be mentioned acetic acid,methanesulfonic acid, p-toluenesulfonic acid, etc.

In the above-mentioned general formula [I], it is preferred that

-   R¹ and R² may be the same or different and are each a methyl group    or an ethyl group;-   R³; R⁴, R⁵ and R⁶ are each a hydrogen atom;-   n is an integer of 2; and-   Y is a thiophen-3-yl group [the 2- and 4-positions of the group are    substituted with same or different groups selected from halogen    atoms, alkyl groups, haloalkyl groups, alkoxyalkyl groups,    cycloalkyl groups, alkoxy groups, haloalkoxy groups, acyl groups,    haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group and    carbamoyl group (its nitrogen atom may be substituted with same or    different alkyl groups)], or

a pyrazol-4-yl group [the 3- and 5-positions of the group aresubstituted with same or different groups selected from halogen atoms,alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups,alkoxy groups, haloalkoxy groups, cycloalkylalkyloxy groups, optionallysubstituted phenoxy group, alkylthio groups, alkylsulfonyl groups, acylgroups, haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group andcarbamoyl group (its nitrogen atom may be substituted with same ordifferent alkyl groups); the 1-position is substituted with hydrogenatom, alkyl group, alkyl group mono-substituted with a group selectedfrom the substituent group β, haloalkyl group, cycloalkyl group, alkenylgroup, alkynyl group, alkylsulfonyl group, alkylsulfonyl groupmono-substituted with a group selected from the substituent group γ,haloalkylsulfonyl group, optionally substituted phenyl group, optionallysubstituted aromatic heterocyclic group, optionally substitutedphenylsulfonyl group, optionally substituted aromaticheterocyclicsulfonyl group, acyl group, haloalkylcarbonyl group,optionally substituted benzylcarbonyl group, optionally substitutedbenzoyl group, alkoxycarbonyl group, optionally substitutedbenzyloxycarbonyl group, optionally substituted phenoxycarbonyl group orcarbamoyl group (its nitrogen atom may be substituted with same ordifferent groups selected from alkyl groups and optionally substitutedphenyl group)], or

a pyrazol-5-yl group [the 4-position of the group is substituted withhalogen atom, alkyl group, haloalkyl group, alkoxyalkyl group,haloalkoxy group, acyl group, haloalkylcarbonyl group, alkoxycarbonylgroup, cyano group or carbamoyl group (its nitrogen atom maybesubstituted with same or different alkyl groups); the 1-position issubstituted with hydrogen atom, alkyl group, alkyl groupmono-substituted with a group selected from the substituent group β,haloalkyl group, cycloalkyl group; or optionally substituted phenylgroup], or

an isoxazol-4-yl group [the 3- and 5-positions of the group aresubstituted with same or different groups selected from halogen atoms,alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups,alkoxy groups, haloalkoxy groups, alkylthio groups, alkylsulfonylgroups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups,cyano group and carbamoyl group (its nitrogen atom may be substitutedwith same or different alkyl groups)], or

an isothiazol-4-yl group -[the 3- and 5-positions of the group aresubstituted with same or different groups selected from halogen atoms,alkyl groups,haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups,alkoxy groups, haloalkoxy groups, optionally substituted phenoxy group,alkylthio groups, alkylsulfonyl groups, acyl groups, haloalkylcarbonylgroups, alkoxycarbonyl groups, cyano group and carbamoyl group (itsnitrogen atom may be substituted with same or different alkyl groups)],or

a pyridin-3-yl group [the 2- and 4-positions of the group aresubstituted with same or different groups selected from halogen atoms,alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups,alkoxy groups, haloalkoxy groups, alkylthio groups, alkylsulfonylgroups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups,cyano group and carbamoyl group (its nitrogen atom may be substitutedwith same or different alkyl groups)], or

a pyrimidin-5-yl group [the 4- and 6-positions of the group aresubstituted with same or different groups selected from halogen atoms,alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups,alkoxy groups, haloalkoxy groups, alkylthio groups, alkylsulfonylgroups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups,cyano group and carbamoyl group (its nitrogen atom may be substitutedwith same or different alkyl groups)].

Next, representative examples of the present compound represented by thegeneral formula [I] are shown in Tables 1 to 10. However, the presentcompound is not restricted to these examples.

The following abbreviated expressions used in the Tables refer to thefollowing groups.

Me: methyl group Et: ethyl group Pr: n-propyl group Pr-i: isopropylgroup Pr-c: cyclopropyl roup Bu: n-butyl group Bu-i: isobutyl groupBu-s: sec-butyl group Bu-t: tert-butyl group Bu-c: cyclobutyl group Pen:n-pentyl group Pen-c: cyclopentyl group Hex: n-hexyl group Hex-c:cyclohexyl group Ph: phenyl group

For example, (4-Cl)Ph indicates 4-chlorophenyl group, and 3-Hexindicates 3-hexyl group.

When the present compound contains hydroxyl group as a substituent,there may exist keto-enol tautomers. Any of these tautomers and anymixture of these tautomers are included in the present compound.

TABLE 1

R¹ R² R³ R⁴ n R⁵ R⁶ Z¹ R²² R²³ R²⁴ Me Me H H 2 H H S Me H H Me Me H H 2H H S Cl Me H Me Me H H 2 H H S H H Me Me Me H H 2 H H S Cl H H Me Me HH 2 H H S H H Cl Me Me H H 2 H H S Cl Cl Cl Me Me H H 2 H H S Ome H H MeMe H H 2 H H S OEt H H Me Me H H 2 H H S OCHF₂ H H Me Me H H 2 H H SOCH₂Ph H H Me Me H H 2 H H O H H H Me Me H H 2 H H O H H C(═O)Ome Me MeH H 2 H H NMe Me H Me Me Me H H 2 H H NMe Me C(═O)OMe CH₂C(═O)OMe Me MeH H 2 H H NMe Me C(═O)OEt CH₂C(═O)OEt Me Me H H 2 H H NMe Me Me Me Me MeH H 2 H H NPh OMe H H Me Me H H 2 H H NPh OEt H H Me Me H H 2 H H NPhOCHF₂ H H H H H H 2 H H S OCHF₂ H H Me H H H 2 H H S OCHF₂ H H Me H Me H2 H H S OCHF₂ H H Me Me H H 2 Me H S OCHF₂ H H Me Me H H 2 Et H S OCHF₂H H Me Me H H 2 Pr-i H S OCHF₂ H H Me Me H H 2 Me Me S OCHF₂ H H Me Et HH 2 H H S OCHF₂ H H Et Et H H 2 H H S OCHF₂ H H Me Pr-i H H 2 H H SOCHF₂ H H Me Pr H H 2 H H S OCHF₂ H H Me Pr-c H H 2 H H S OCHF₂ H H MeCH₂Pr-c H H 2 H H S OCHF₂ H H —(CH₂)₂— H H 2 H H S Cl Cl Cl —(CH₂)₃— H H2 H H S Cl Cl Cl —(CH₂)₄— H H 2 H H S Cl Cl Cl —(CH₂)₅— H H 2 H H S ClCl Cl H —(CH₂)₃— H 2 H H S Cl Cl Cl H —(CH₂)₄— H 2 H H S Cl Cl Cl H—(CH₂)₅— H 2 H H S Cl Cl Cl H —(CH₂)₆— H 2 H H S Cl Cl Cl Me Me H H 1 HH S Me H H Me Me H H 1 H H S Cl Me H Me Me H H 1 H H S H H Me Me Me H H1 H H S Cl H H Me Me H H 1 H H S H H Cl Me Me H H 1 H H S Cl Cl Cl Me MeH H 1 H H S OMe H H Me Me H H 1 H H S OEt H H Me Me H H 1 H H S OCHF₂ HH Me Me H H 1 H H S OCH₂Ph H H Me Me H H 1 H H O H H H Me Me H H 1 H H OH H C(═O)Ome Me Me H H 1 H H NMe Me H Me Me Me H H 1 H H NMe Me C(═O)OMeCH₂C(═O)OMe Me Me H H 1 H H NMe Me C(═O)OEt CH₂C(═O)OEt Me Me H H 1 H HNMe Me Me Me Me Me H H 1 H H NPh OMe H H Me Me H H 1 H H NPh OEt H H MeMe H H 1 H H NPh OCHF₂ H H H H H H 1 H H S OCHF₂ H H Me H H H 1 H H SOCHF₂ H H Me H Me H 1 H H S OCHF₂ H H Me Me H H 1 Me H S OCHF₂ H H Me MeH H 1 Et H S OCHF₂ H H Me Me H H 1 Pr-i H S OCHF₂ H H Me Me H H 1 Me MeS OCHF₂ H H Me Et H H 1 H H S OCHF₂ H H Et Et H H 1 H H S OCHF₂ H H MePr-i H H 1 H H S OCHF₂ H H Me Pr H H 1 H H S OCHF₂ H H Me Pr-c H H 1 H HS OCHF₂ H H Me CH₂Pr-c H H 1 H H S OCHF₂ H H —(CH₂)₂— H H 1 H H S Cl ClCl —(CH₂)₃— H H 1 H H S Cl Cl Cl —(CH₂)₄— H H 1 H H S Cl Cl Cl —(CH₂)₅—H H 1 H H S Cl Cl Cl H —(CH₂)₃— H 1 H H S Cl Cl Cl H —(CH₂)₄— H 1 H H SCl Cl Cl H —(CH₂)₅— H 1 H H S Cl Cl Cl H —(CH₂)₆— H 1 H H S Cl Cl Cl MeMe H H 0 H H S Me H H Me Me H H 0 H H S Cl Me H Me Me H H 0 H H S H H MeMe Me H H 0 H H S Cl H H Me Me H H 0 H H S H H Cl Me Me H H 0 H H S ClCl Cl Me Me H H 0 H H S OMe H H Me Me H H 0 H H S OEt H H Me Me H H 0 HH S OCHF₂ H H Me Me H H 0 H H S OCH₂Ph H H Me Me H H 0 H H O H H H Me MeH H 0 H H O H H C(═O)Ome Me Me H H 0 H H NMe Me H Me Me Me H H 0 H H NMeMe C(═O)OMe CH₂C(═O)OMe Me Me H H 0 H H NMe Me C(═O)OEt CH₂C(═O)OEt MeMe H H 0 H H NMe Me Me Me Me Me H H 0 H H NPh OMe H H Me Me H H 0 H HNPh OEt H H Me Me H H 0 H H NPh OCHF₂ H H H H H H 0 H H S OCHF₂ H H Me HH H 0 H H S OCHF₂ H H Me H Me H 0 H H S OCHF₂ H H Me Me H H 0 Me H SOCHF₂ H H Me Me H H 0 Et H S OCHF₂ H H Me Me H H 0 Pr-i H S OCHF₂ H H MeMe H H 0 Me Me S OCHF₂ H H Me Et H H 0 H H S OCHF₂ H H Et Et H H 0 H H SOCHF₂ H H Me Pr-i H H 0 H H S OCHF₂ H H Me Pr H H 0 H H S OCHF₂ H H MePr-c H H 0 H H S OCHF₂ H H Me CH₂Pr-c H H 0 H H S OCHF₂ H H —(CH₂)₂— H H0 H H S Cl Cl Cl —(CH₂)₃— H H 0 H H S Cl Cl Cl —(CH₂)₄— H H 0 H H S ClCl Cl —(CH₂)₅— H H 0 H H S Cl Cl Cl H —(CH₂)₃— H 0 H H S Cl Cl Cl H—(CH₂)₄— H 0 H H S Cl Cl Cl H —(CH₂)₅— H 0 H H S Cl Cl Cl H —(CH₂)₆— H 0H H S Cl Cl Cl Me Et H H 2 H H S H H H Me Et H H 2 H H O H H H Me Et H H2 H H NH H H H

TABLE 2

R¹ R² R³ R⁴ n R⁵ R⁶ Z² R²⁵ R²⁶ R²⁷ Me Me H H 2 H H S H H H Me Me H H 2 HH S H OMe H Me Me H H 2 H H S Cl H Cl Me Me H H 2 H H S Cl Cl Cl Me Me HH 2 H H S Cl Me H Me Me H H 2 H H S NHMe Me H Me Me H H 2 H H S N(Me)₂Me H Me Me H H 2 H H S NHC(═O)Me Me H Me Me H H 2 H H S NHC(═O)Ph Me HMe Me H H 2 H H S NHSO₂Me Me H Me Me H H 2 H H S NHSO₂Ph Me H Me Me H H2 H H S Me Me Me Me Me H H 2 H H S Me C(═O)OMe Me Me Me H H 2 H H S MeC(═O)OEt Me Me Me H H 2 H H S Me C(═O)OPh Me Me Me H H 2 H H S Me CN MeMe Me H H 2 H H S Me C(═O)NHMe Me Me Me H H 2 H H S Me C(═O)Me Me Me MeH H 2 H H S Me C(═O)Et Me Me Me H H 2 H H S Me C(═O)Pr-i Me Me Me H H 2H H S Me C(═O)Pr Me Me Me H H 2 H H S Me C(═O)CF₃ Me Me Me H H 2 H H SMe C(NOMe)Me Me Me Me H H 2 H H S Ph C(═O)Me Me Me Me H H 2 H H S PhC(═NOMe)Me Me Me Me H H 2 H H S CF₃ OMe H Me Me H H 2 H H S CF₃ OEt H MeMe H H 2 H H S CF₃ OPr-i H Me Me H H 2 H H S CF₃ OPr-i H Me Me H H 2 H HS CF₃ OCHF₂ H Me Me H H 2 H H S Cl Me H Me Me H H 2 H H S Cl Me Me Me MeH H 2 H H S Cl C(═O)OMe Cl Me Me H H 2 H H S Cl CN Cl Me Me H H 2 H H SCl C(═O)NHMe Cl Me Me H H 2 H H S Cl C(═O)N(Me)₂ Cl Me Me H H 2 H H S ClC(═O)Me Cl Me Me H H 2 H H S Cl C(═O)Et Cl Me Me H H 2 H H S ClC(═O)Pr-i Cl Me Me H H 2 H H S Cl C(═O)Pr Cl Me Me H H 2 H H S ClC(═O)CF₃ Cl Me Me H H 2 H H S Cl C(═NOMe)Me Cl Me Me H H 2 H H O H H HMe Me H H 2 H H O Me H Cl H H H H 2 H H S Cl Cl Cl Me H H H 2 H H S ClCl Cl Me H Me H 2 H H S Cl Cl Cl Me Me H H 2 Me H S Cl Cl Cl Me Me H H 2Et H S Cl Cl Cl Me Me H H 2 Pr-i H S Cl Cl Cl Me Me H H 2 Me Me S Cl ClCl Me Et H H 2 H H S Cl Cl Cl Et Ft H H 2 H H S Cl Cl Cl Me Pr-i H H 2 HH S Cl Cl Cl Me Pr H H 2 H H S Cl Cl Cl Me Pr-c H H 2 H H S Cl Cl Cl MeCH₂Pr-c H H 2 H H S Cl Cl Cl —(CH₂)₂— H H 2 H H S Cl Cl Cl —(CH₂)₃— H H2 H H S Cl Cl Cl —(CH₂)₄— H H 2 H H S Cl Cl Cl —(CH₂)₅— H H 2 H H S ClCl Cl H —(CH₂)₃— H 2 H H S Cl Cl Cl H —(CH₂)₄— H 2 H H S Cl Cl Cl H—(CH₂)₅— H 2 H H S Cl Cl Cl H —(CH₂)₆— H 2 H H S Cl Cl Cl Me Me H H 1 HH S H H H Me Me H H 1 H H S H OMe H Me Me H H 1 H H S Cl H Cl Me Me H H1 H H S Cl Cl Cl Me Me H H 1 H H S Cl Me H Me Me H H 1 H H S NHMe Me HMe Me H H 1 H H S N(Me)₂ Me H Me Me H H 1 H H S NHC(═O)Me Me H Me Me H H1 H H S NHC(═O)Ph Me H Me Me H H 1 H H S NHSO₂Me Me H Me Me H H 1 H H SNHSO₂Ph Me H Me Me H H 1 H H S Me Me Me Me Me H H 1 H H S Me C(═O)OMe MeMe Me H H 1 H H S Me C(═O)OEt Me Me Me H H 1 H H S Me C(═O)OPh Me Me MeH H 1 H H S Me CN Me Me Me H H 1 H H S Me C(═O)NHMe Me Me Me H H 1 H H SMe C(═O)Me Me Me Me H H 1 H H S Me C(═O)Et Me Me Me H H 1 H H S MeC(═O)Pr-i Me Me Me H H 1 H H S Me C(═O)Pr Me Me Me H H 1 H H S MeC(═O)CF₃ Me Me Me H H 1 H H S Me C(═NOMe)Me Me Me Me H H 1 H H S PhC(═O)Me Me Me Me H H 1 H H S Ph C(═NOMe)Me Me Me Me H H 1 H H S CF₃ OMeH Me Me H H 1 H H S CF₃ OEt H Me Me H H 1 H H S CF₃ OPr-i H Me Me H H 1H H S CF₃ OPr-i H Me Me H H 1 H H S CF₃ OCHF₂ H Me Me H H 1 H H S Cl MeH Me Me H H 1 H H S Cl Me Me Me Me H H 1 H H S Cl C(═O)OMe Cl Me Me H H1 H H S Cl CN Cl Me Me H H 1 H H S Cl C(═O)NHMe Cl Me Me H H 1 H H S ClC(═O)N(Me)₂ Cl Me Me H H 1 H H S Cl C(═O)Me Cl Me Me H H 1 H H S ClC(═O)Et Cl Me Me H H 1 H H S Cl C(═O)Pr-i Cl Me Me H H 1 H H S ClC(═O)Pr Cl Me Me H H 1 H H S Cl C(═O)CF₃ Cl Me Me H H 1 H H S ClC(═NOMe)Me Cl Me Me H H 1 H H O H H H Me Me H H 1 H H O Me H Cl H H H H1 H H S Cl Cl Cl Me H H H 1 H H S Cl Cl Cl Me H Me H 1 H H S Cl Cl Cl MeMe H H 1 Me H S Cl Cl Cl Me Me H H 1 Et H S Cl Cl Cl Me Me H H 1 Pr-i HS Cl Cl Cl Me Me H H 1 Me Me S C1 Cl Cl Me Et H H 1 H H S Cl Cl Cl Et EtH H 1 H H S Cl Cl Cl Me Pr-i H H 1 H H S Cl Cl Cl Me Pr H H 1 H H S ClCl Cl Me Pr-c H H 1 H H S Cl Cl Cl Me CH₂Pr-c H H 1 H H S Cl Cl Cl—(CH₂)₂— H H 1 H H S Cl Cl Cl —(CH₂)₃— H H 1 H H S Cl Cl Cl —(CH₂)₄— H H1 H H S Cl Cl Cl —(CH₂)₅— H H 1 H H S Cl Cl Cl H —(CH₂)₃— H 1 H H S ClCl Cl H —(CH₂)₄— H 1 H H S Cl Cl Cl H —(CH₂)₅— H 1 H H S Cl Cl Cl H—(CH₂)₆— H 1 H H S Cl Cl Cl Me Me H H 0 H H S H H H Me Me H H 0 H H S HOMe H Me Me H H 0 H H S Cl H Cl Me Me H H 0 H H S Cl Cl Cl Me Me H H 0 HH S Cl Me H Me Me H H 0 H H S NHMe Me H Me Me H H 0 H H S N(Me)₂ Me H MeMe H H 0 H H S NHC(═O)Me Me H Me Me H H 0 H H S NHC(═O)Ph Me H Me Me R H0 H H S NHSO₂Me Me H Me Me H H 0 H H S NHSO₂Ph Me H Me Me H H 0 H H S MeMe Me Me Me H H 0 H H S Me C(═O)OMe Me Me Me H H 0 H H S Me C(═O)OEt MeMe Me H H 0 H H S Me C(═O)OPh Me Me Me H H 0 H H S Me CN Me Me Me H H 0H H S Me C(═O)NHMe Me Me Me H H 0 H H S Me C(═O)Me Me Me Me H H 0 H H SMe C(═O)Et Me Me Me H H 0 H H S Me C(═O)Pr-i Me Me Me H H 0 H H S MeC(═O)Pr Me Me Me H H 0 H H S Me C(═O)CF₃ Me Me Me H H 0 H H S MeC(═NOMe)Me Me Me Me H H 0 H H S Ph C(═O)Me Me Me Me H H 0 H H S PhC(═NOMe)Me Me Me Me H H 0 H H S CF₃ OMe H Me Me H H 0 H H S CF₃ OEt H MeMe H H 0 H H S CF₃ OPr-i H Me Me H H 0 H H S CF₃ OPr-i H Me Me H H 0 H HS CF₃ OCHF₂ H Me Me H H 0 H H S Cl Me H Me Me H H 0 H H S Cl Me Me Me MeH H 0 H H S Cl C(═O)OMe Cl Me Me H H 0 H H S Cl CN Cl Me Me H H 0 H H SCl C(═O)NHMe Cl Me Me H H 0 H H S Cl C(═O)N(Me)₂ Cl Me Me H H 0 H H S ClC(═O)Me Cl Me Me H H 0 H H S Cl C(═O)Et Cl Me Me H H 0 H H S ClC(═O)Pr-i Cl Me Me H H 0 H H S Cl C(═O)Pr Cl Me Me H H 0 H H S ClC(═O)CF₃ Cl Me Me H H 0 H H S Cl C(═NOMe)Me Cl Me Me H H 0 H H O H H HMe Me H H 0 H H O Me H Cl H H H H 0 H H S Cl Cl Cl Me H H H 0 H H S ClCl Cl Me H Me H 0 H H S Cl Cl Cl Me Me H H 0 Me H S Cl Cl Cl Me Me H H 0Et H S Cl Cl Cl Me Me H H 0 Pr-i H S Cl Cl Cl Me Me H H 0 Me Me S Cl ClCl Me Et H H 0 H H S Cl Cl Cl Et Et H H 0 H H S Cl Cl Cl Me Pr-i H H 0 HH S Cl Cl Cl Me Pr H H 0 H H S Cl Cl Cl Me Pr-c H H 0 H H S Cl Cl Cl MeCH₂Pr-c H H 0 H H S Cl Cl Cl —(CH₂)₂— H H 0 H H S Cl Cl Cl —(CH₂)₃— H H0 H H S Cl Cl Cl —(CH₂)₄— H H 0 H H S Cl Cl Cl —(CH₂)₅— H H 0 H H S ClCl Cl H —(CH₂)₃— H 0 H H S Cl Cl Cl H —(CH₂)₄— H 0 H H S Cl Cl Cl H—(CH₂)₅— H 0 H H S Cl Cl Cl H —(CH₂)₆— H 0 H H S Cl Cl Cl

TABLE 3

R¹ R² R³ R⁴ n R⁵ R⁶ R²⁹ R²⁸ R³⁰ Me Me H H 2 H H Cl H Cl Me Me H H 2 H HOCHF₂ H Cl Me Me H H 2 H H OCHF₂ H OCHF₂ Me Me H H 2 H H Me H Cl Me Me HH 2 H H Me H OCHF₂ Me Me H H 2 H H CHF₂ H Cl Me Me H H 2 H H CHF₂ HOCHF₂ Me Me H H 2 H H CF₃ H F Me Me H H 2 H H CF₃ H Cl Me Me H H 2 H HCF₃ H OMe Me Me H H 2 H H CF₃ H OEt Me Me H H 2 H H CF₃ H OCHF₂ Me Me HH 2 H H CF₃ H CN Me Me H H 2 H H CF₃ H Me Me Me H H 2 H H H Me Cl Me MeH H 2 H H Me Me Me Me Me H H 2 H H Me Me F Me Me H H 2 H H F Me Me Me MeH H 2 H H Me Me Cl Me Me H H 2 H H Cl Me Me Me Me H H 2 H H Me Me OMe MeMe H H 2 H H OMe Me Me Me Me H H 2 H H Me Me OCHF₂ Me Me H H 2 H H OCHF₂Me Me Me Me H H 2 H H Me Me CN Me Me H H 2 H H CN Me Me Me Me H H 2 H HEt Me F Me Me H H 2 H H F Me Et Me Me H H 2 H H Et Me Cl Me Me H H 2 H HCl Me Et Me Me H H 2 H H Et Me OMe Me Me H H 2 H H OMe Me Et Me Me H H 2H H Et Me OCHF₂ Me Me H H 2 H H OCHF₂ Me Et Me Me H H 2 H H Et Me CN MeMe H H 2 H H CN Me Et Me Me H H 2 H H Pr-i Me F Me Me H H 2 H H F MePr-i Me Me H H 2 H H Pr-i Me Cl Me Me H H 2 H H Cl Me Pr-i Me Me H H 2 HH Pr-i Me OMe Me Me H H 2 H H OMe Me Pr-i Me Me H H 2 H H Pr-i Me OCHF₂Me Me H H 2 H H OCHF₂ Me Pr-i Me Me H H 2 H H Pr-i Me CN Me Me H H 2 H HCN Me Pr-i Me Me H H 2 H H Bu-t Me F Me Me H H 2 H H F Me Bu-t Me Me H H2 H H Bu-t Me Cl Me Me H H 2 H H Cl Me Bu-t Me Me H H 2 H H Bu-t Me OMeMe Me H H 2 H H OMe Me Bu-t Me Me H H 2 H H Bu-t Me OCHF₂ Me Me H H 2 HH OCHF₂ Me Bu-t Me Me H H 2 H H Bu-t Me CN Me Me H H 2 H H CN Me Bu-t MeMe H H 2 H H CH₂OMe Me F Me Me H H 2 H H F Me CH₂OMe Me Me H H 2 H HCH₂OMe Me Cl Me Me H H 2 H H Cl Me CH₂OMe Me Me H H 2 H H CH₂OMe Me OMeMe Me H H 2 H H OMe Me CH₂OMe Me Me H H 2 H H CH₂OMe Me OCHF₂ Me Me H H2 H H OCHF₂ Me CH₂OMe Me Me H H 2 H H CH₂OMe Me CN Me Me H H 2 H H CN MeCH₂OMe Me Me H H 2 H H Cl Me Cl Me Me H H 2 H H CHF₂ Me Cl Me Me H H 2 HH Cl Me CHF₂ Me Me H H 2 H H OCHF₂ Me H Me Me H H 2 H H OCHF₂ Me F Me MeH H 2 H H F Me OCHF₂ Me Me H H 2 H H OCHF₂ Me Cl Me Me H H 2 H H Cl MeOCHF₂ Me Me H H 2 H H OCHF₂ Me OMe Me Me H H 2 H H OMe Me OCHF₂ Me Me HH 2 H H OCHF₂ Me OCHF₂ Me Me H H 2 H H OCHF₂ Me CN Me Me H H 2 H H CN MeOCHF₂ Me Me H H 2 H H CF₃ Me H Me Me H H 2 H H CF₃ Me Cl Me Me H H 2 H HCl Me CF₃ Me Me H H 2 H H CF₃ Me Br Me Me H H 2 H H Br Me CF₃ Me Me H H2 H H CF₃ Me I Me Me H H 2 H H I Me CF₃ Me Me H H 2 H H CF₃ Me F Me Me HH 2 H H F Me CF₃ Me Me H H 2 H H CF₃ Me OH Me Me H H 2 H H OH Me CF₃ MeMe H H 2 H H CF₃ Me OMe Me Me H H 2 H H OMe Me CF₃ Me Me H H 2 H H CF₃Me OEt Me Me H H 2 H H OEt Me CF₃ Me Me H H 2 H H CF₃ Me OPr-i Me Me H H2 H H CF₃ Me OPr Me Me H H 2 H H CF₃ Me OBu-t Me Me H H 2 H H CF₃ MeOBu-s Me Me H H 2 H H CF₃ Me OBu-i Me Me H H 2 H H CF₃ Me OBu Me Me H H2 H H CF₃ Me O(2-Pen) Me Me H H 2 H H CF₃ Me O(3-Pen) Me Me H H 2 H HCF₃ Me OPen-n Me Me H H 2 H H CF₃ Me O(2-Hex) Me Me H H 2 H H CF₃ MeO(3-Hex) Me Me H H 2 H H CF₃ Me OHex-n Me Me H H 2 H H CF₃ Me OPen-c MeMe H H 2 H H CF₃ Me OHex-c Me Me H H 2 H H CF₃ Me OCH₂Pr-c Me Me H H 2 HH CF₃ Me OCH₂Bu-c Me Me H H 2 H H CF₃ Me OCH₂Pen-c Me Me H H 2 H H CF₃Me OCH₂Hex-c Me Me H H 2 H H CF₃ Me OCH₂CH═CH₂ Me Me H H 2 H H CF₃ MeOCH₂C≡CH Me Me H H 2 H H CF₃ Me OCHF₂ Me Me H H 2 H H OCHF₂ Me CF₃ Me MeH H 2 H H CF₃ Me OCH₂CHF₂ Me Me H H 2 H H OCH₂CHF₂ Me CF₃ Me Me H H 2 HH CF₃ Me OCH₂CF₃ Me Me H H 2 H H OCH₂CF₃ Me CF₃ Me Me H H 2 H H CF₃ MeOCH₂CN Me Me H H 2 H H CF₃ Me OCH₂C(═O)OEt Me Me H H 2 H H CF₃ MeOCH(Me)C(═O)OEt Me Me H H 2 H H CF₃ Me OCH₂C(═O)NH₂ Me Me H H 2 H H CF₃Me OCH₂C(═O)NHMe Me Me H H 2 H H CF₃ Me OCH₂C(═O)N(Me)₂ Me Me H H 2 H HCF₃ Me OCH₂Ph Me Me H H 2 H H CF₃ Me OPh Me Me H H 2 H H CF₃ MeO(2-Cl)Ph Me Me H H 2 H H CF₃ Me O(2-Br)Ph Me Me H H 2 H H CF₃ MeO(2-F)Ph Me Me H H 2 H H CF₃ Me O(2-Me)Ph Me Me H H 2 H H CF₃ MeO(2-OMe)Ph Me Me H H 2 H H CF₃ Me O(2-NO₂)Ph Me Me H H 2 H H CF₃ MeO(2-CN)Ph Me Me H H 2 H H CF₃ Me O(2-C(═O)OMe)Ph Me Me H H 2 H H CF₃ MeO(3-Cl)Ph Me Me H H 2 H H CF₃ Me O(3-Br)Ph Me Me H H 2 H H CF₃ MeO(3-F)Ph Me Me H H 2 H H CF₃ Me O(3-Me)Ph Me Me H H 2 H H CF₃ MeO(3-OMe)Ph Me Me H H 2 H H CF₃ Me O(3-NO₂)Ph Me Me H H 2 H H CF₃ MeO(3-CN)Ph Me Me H H 2 H H CF₃ Me O(3-C(═O)OMe)Ph Me Me H H 2 H H CF₃ MeO(4-Cl)Ph Me Me H H 2 H H CF₃ Me O(4-Br)Ph Me Me H H 2 H H CF₃ MeO(4-F)Ph Me Me H H 2 H H CF₃ Me O(4-Me)Ph Me Me H H 2 H H CF₃ MeO(4-OMe)Ph Me Me H H 2 H H CF₃ Me O(4-NO₂)Ph Me Me H H 2 H H CF₃ MeO(4-CN)Ph Me Me H H 2 H H CF₃ Me O(4-C(═O)OMe)Ph Me Me H H 2 H H CF₃ MeOC(═O)Me Me Me H H 2 H H CF₃ Me OC(═O)Et Me Me H H 2 H H CF₃ MeOC(═O)CH₂Ph Me Me H H 2 H H CF₃ Me OC(═O)CF₃ Me Me H H 2 H H CF₃ MeOC(═O)Ph Me Me H H 2 H H CF₃ Me OSO₂Me Me Me H H 2 H H CF₃ Me OSO₂Et MeMe H H 2 H H CF₃ Me OSO₂CH₂Ph Me Me H H 2 H H CF₃ Me OSO₂CF₃ Me Me H H 2H H CF₃ Me OSO₂Ph Me Me H H 2 H H CF₃ Me SMe Me Me H H 2 H H CF₃ Me SOMeMe Me H H 2 H H CF₃ Me SO₂Me Me Me H H 2 H H CF₃ Me SEt Me Me H H 2 H HCF₃ Me SOEt Me Me H H 2 H H CF₃ Me SO₂Et Me Me H H 2 H H CF₃ Me SPr MeMe H H 2 H H CF₃ Me SOPr Me Me H H 2 H H CF₃ Me SO₂Pr Me Me H H 2 H HCF₃ Me SPr-i Me Me H H 2 H H CF₃ Me SOPr-i Me Me H H 2 H H CF₃ MeSO₂Pr-i Me Me H H 2 H H CF₃ Me SBu-t Me Me H H 2 H H CF₃ Me SOBu-t Me MeH H 2 H H CF₃ Me SO₂Bu-t Me Me H H 2 H H CF₃ Me SCHF₂ Me Me H H 2 H HCF₃ Me SOCHF₂ Me Me H H 2 H H CF₃ Me SO₂CHF₂ Me Me H H 2 H H CF₃ Me SCF₃Me Me H H 2 H H CF₃ Me SOCF₃ Me Me H H 2 H H CF₃ Me SO₂CF₃ Me Me H H 2 HH CF₃ Me SPh Me Me H H 2 H H CF₃ Me SOh Me Me H H 2 H H CF₃ Me SO₂Ph MeMe H H 2 H H CF₃ Me SCH₂Ph Me Me H H 2 H H CF₃ Me SOCH₂Ph Me Me H H 2 HH CF₃ Me SO₂CH₂Ph Me Me H H 2 H H CF₃ Me SCH₂C(═O)OEt Me Me H H 2 H HCF₃ Me SOCH₂C(═O)OEt Me Me H H 2 H H CF₃ Me SO₂CH₂C(═O)OEt Me Me H H 2 HH CF₃ Me SCH(Me)C(═O)OEt Me Me H H 2 H H CF₃ Me SOCH(Me)C(═O)OEt Me Me HH 2 H H CF₃ Me SO₂CH(Me)C(═O)OEt Me Me H H 2 H H CF₃ Me SCH₂C(═O)NH₂ MeMe H H 2 H H CF₃ Me SOCH₂C(═O)NH₂ Me Me H H 2 H H CF₃ Me SO₂CH₂C(═O)NH₂Me Me H H 2 H H CF₃ Me SCH₂C(═O)NHMe Me Me H H 2 H H CF₃ MeSOCH₂C(═O)NHMe Me Me H H 2 H H CF₃ Me SO₂CH₂C(═O)NHMe Me Me H H 2 H HCF₃ Me SCH₂C(═O)N(Me)₂ Me Me H H 2 H H CF₃ Me SOCH₂C(═O)N(Me)₂ Me Me H H2 H H CF₃ Me SO₂CH₂C(═O)N(Me)₂ Me Me H H 2 H H CF₃ Me NH₂ Me Me H H 2 HH CF₃ Me NHMe Me Me H H 2 H H CF₃ Me N(Me)₂ Me Me H H 2 H H CF₃ MeNHC(═O)Me Me Me H H 2 H H CF₃ Me N(Me)C(═O)Me Me Me H H 2 H H CF₃ MeNHSO₂Me Me Me H H 2 H H CF₃ Me N(Me)SO₂Me Me Me H H 2 H H CF₃ MeNHSO₂CHF₂ Me Me H H 2 H H CF₃ Me N(Me)SO₂CHF₂ Me Me H H 2 H H CF₃ MeNHSO₂CF₃ Me Me H H 2 H H CF₃ Me N(Me)SO₂CF₃ Me Me H H 2 H H CF₃ Me NHPhMe Me H H 2 H H CF₃ Me N(Me)Ph Me Me H H 2 H H CF₃ Me CN Me Me H H 2 H HCN Me CF₃ Me Me H H 2 H H CF₃ Me C(═O)OMe Me Me H H 2 H H CF₃ MeC(═O)OPr-i Me Me H H 2 H H CF₃ Me C(═O)OCH₂Ph Me Me H H 2 H H CF₃ MeC(═O)OPh Me Me H H 2 H H CF₃ Me C(═O)NH₂ Me Me H H 2 H H CF₃ MeC(═O)NHMe Me Me H H 2 H H CF₃ Me C(═O)N(Me)₂ Me Me H H 2 H H CF₃ MeC(═O)Me Me Me H H 2 H H CF₃ Me C(═O)CF₃ Me Me H H 2 H H CF₃ MeC(═O)CH₂Ph Me Me H H 2 H H CF₃ Me C(═O)Ph Me Me H H 2 H H CF₃ Me Me MeMe H H 2 H H Me Me CF₃ Me Me H H 2 H H CF₃ Me Et Me Me H H 2 H H CF₃ MePr-i Me Me H H 2 H H CF₃ Me Pr Me Me H H 2 H H CF₃ Me CH₂OMe Me Me H H 2H H CF₃ Me CF₃ Me Me H H 2 H H CF₃ Me CHF₂ Me Me H H 2 H H CF₃ Me Ph MeMe H H 2 H H CF₂CF₃ Me Cl Me Me H H 2 H H CN Me F Me Me H H 2 H H F MeCN Me Me H H 2 H H CN Me Cl Me Me H H 2 H H Cl Me CN Me Me H H 2 H H CNMe CN Me Me H H 2 H H COOMe Me F Me Me H H 2 H H F Me COOMe Me Me H H 2H H COOMe Me Cl Me Me H H 2 H H Cl Me COOMe Me Me H H 2 H H SO₂Me Me ClMe Me H H 2 H H Cl Me SO₂Me Me Me H H 2 H H Ph Me Me Me Me H H 2 H H PhMe Cl Me Me H H 2 H H Ph Me QEt Me Me H H 2 H H Ph Me CF₃ Me Me H H 2 HH Ph Me Ph Me Me H H 2 H H Me Et OCHF₂ Me Me H H 2 H H OCHF₂ Et Me Me MeH H 2 H H Me Et CN Me Me H H 2 H H CN Et Me Me Me H H 2 H H Pr-i EtOCHF₂ Me Me H H 2 H H OCHF₂ Et Pr-i Me Me H H 2 H H Pr-i Et CN Me Me H H2 H H CN Et Pr-i Me Me H H 2 H H Cl Et Cl Me Me H H 2 H H OCHF₂ Et Cl MeMe H H 2 H H Cl Et OCHF₂ Me Me H H 2 H H OCHF₂ Et OCHF₂ Me Me H H 2 H HCF₃ Et F Me Me H H 2 H H F Et CF₃ Me Me H H 2 H H CF₃ Et Cl Me Me H H 2H H Cl Et CF₃ Me Me H H 2 H H CF₃ Et OMe Me Me H H 2 H H OMe Et CF₃ MeMe H H 2 H H CF₃ Et OEt Me Me H H 2 H H OEt Et CF₃ Me Me H H 2 H H CF₃Et OCHF₂ Me Me H H 2 H H OCHF₂ Et CF₃ Me Me H H 2 H H CF₃ Et CN Me Me HH 2 H H CN Et CF₃ Me Me H H 2 H H CF₃ Et Me Me Me H H 2 H H Me Et CF₃ MeMe H H 2 H H Me Pr-i OCHF₂ Me Me H H 2 H H OCHF₂ Pr-i Me Me Me H H 2 H HMe Pr-i CN Me Me H H 2 H H CN Pr-i Me Me Me H H 2 H H Pr-i Pr-i OCHF₂ MeMe H H 2 H H OCHF₂ Pr-i Pr-i Me Me H H 2 H H Pr-i Pr-i CN Me Me H H 2 HH CN Pr-i Pr-i Me Me H H 2 H H Cl Pr-i Cl Me Me H H 2 H H OCHF₂ Pr-i ClMe Me H H 2 H H Cl Pr-i OCHF₂ Me Me H H 2 H H OCHF₂ Pr-i OCHF₂ Me Me H H2 H H CF₃ Pr-i F Me Me H H 2 H H F Pr-i CF₃ Me Me H H 2 H H CF₃ Pr-i ClMe Me H H 2 H H Cl Pr-i CF₃ Me Me H H 2 H H CF₃ Pr-i OMe Me Me H H 2 H HOMe Pr-i CF₃ Me Me H H 2 H H CF₃ Pr-i OEt Me Me H H 2 H H OEt Pr-i CF₃Me Me H H 2 H H CF₃ Pr-i OCHF₂ Me Me H H 2 H H OCHF₂ Pr-i CF₃ Me Me H H2 H H CF₃ Pr-i CN Me Me H H 2 H H CN Pr-i CF₃ Me Me H H 2 H H CF₃ Pr-iMe Me Me H H 2 H H Me Pr-i CF₃ Me Me H H 2 H H Me Pr OCHF₂ Me Me H H 2 HH OCHF₂ Pr Me Me Me H H 2 H H Me Pr CN Me Me H H 2 H H CN Pr Me Me Me HH 2 H H Pr-i Pr OCHF₂ Me Me H H 2 H H OCHF₂ Pr Pr-i Me Me H H 2 H H Pr-iPr CN Me Me H H 2 H H CN Pr Pr-i Me Me H H 2 H H Cl Pr Cl Me Me H H 2 HH OCHF₂ Pr Cl Me Me H H 2 H H Cl Pr OCHF₂ Me Me H H 2 H H OCHF₂ Pr OCHF₂Me Me H H 2 H H CF₃ Pr F Me Me H H 2 H H F Pr CF₃ Me Me H H 2 H H CF₃ PrCl Me Me H H 2 H H Cl Pr CF₃ Me Me H H 2 H H CF₃ Pr OMe Me Me H H 2 H HOMe Pr CF₃ Me Me H H 2 H H CF₃ Pr OEt Me Me H H 2 H H OEt Pr CF₃ Me Me HH 2 H H CF₃ Pr OCHF₂ Me Me H H 2 H H OCHF₂ Pr CF₃ Me Me H H 2 H H CF₃ PrCN Me Me H H 2 H H CN Pr CF₃ Me Me H H 2 H H CF₃ Pr Me Me Me H H 2 H HMe Pr CF₃ Me Me H H 2 H H Me Bu-t F Me Me H H 2 H H Me Bu-t Cl Me Me H H2 H H Me Bu-t OCHF₂ Me Me H H 2 H H Me Bu-t CN Me Me H H 2 H H Cl Bu-tCl Me Me H H 2 H H OCHF₂ Bu-t Cl Me Me H H 2 H H OCHF₂ Bu-t OCHF₂ Me MeH H 2 H H CF₃ Bu-t H Me Me H H 2 H H CF₃ Bu-t F Me Me H H 2 H H CF₃ Bu-tCl Me Me H H 2 H H Cl Bu-t CF₃ Me Me H H 2 H H CF₃ Bu-t OMe Me Me H H 2H H OMe Bu-t CF₃ Me Me H H 2 H H CF₃ Bu-t OEt Me Me H H 2 H H OEt Bu-tCF₃ Me Me H H 2 H H CF₃ Bu-t OCHF₂ Me Me H H 2 H H CF₃ Bu-t CN Me Me H H2 H H CF₃ Bu-t Me Me Me H H 2 H H Me Bu-t CF₃ Me Me H H 2 H H CF₃ Bu-sCl Me Me H H 2 H H Cl Bu-s CF₃ Me Me H H 2 H H CF₃ Bu-i Cl Me Me H H 2 HH Cl Bu-i CF₃ Me Me H H 2 H H CF₃ Bu Cl Me Me H H 2 H H Cl Bu CF₃ Me MeH H 2 H H CF₃ 1-Methylbutyl Cl Me Me H H 2 H H Cl 1-Methylbutyl CF₃ MeMe H H 2 H H CF₃ 1-Ethylpropyl Cl Me Me H H 2 H H Cl 1-Ethylpropyl CF₃Me Me H H 2 H H CF₃ 1-Pentyl Cl Me Me H H 2 H H Cl 1-Pentyl CF₃ Me Me HH 2 H H CF₃ 1-Methylpentyl Cl Me Me H H 2 H H Cl 1-Methylpentyl CF₃ MeMe H H 2 H H CF₃ 2-Ethylbutyl Cl Me Me H H 2 H H Cl 2-Ethylbutyl CF₃ MeMe H H 2 H H CF₃ 3,3-Dimethylbutyl Cl Me Me H H 2 H H Cl3,3-Dimethylbutyl CF₃ Me Me H H 2 H H CF₃ 1-Hexyl Cl Me Me H H 2 H H Cl1-Hexyl CF₃ Me Me H H 2 H H CF₃ 1-Heptyl Cl Me Me H H 2 H H Cl 1-HeptylCF₃ Me Me H H 2 H H CF₃ 1-Octyl Cl Me Me H H 2 H H Cl 1-Octyl CF₃ Me MeH H 2 H H CF₃ CH₂Ph Cl Me Me H H 2 H H Cl CH₂Ph CF₃ Me Me H H 2 H H CF₃Pr-c F Me Me H H 2 H H CF₃ Pr-c Cl Me Me H H 2 H H CF₃ Pr-c OMe Me Me HH 2 H H CF₃ Pr-c OCHF₂ Me Me H H 2 H H CF₃ Pr-c CN Me Me H H 2 H H CF₃Pen-c Cl Me Me H H 2 H H Cl Pen-c CF₃ Me Me H H 2 H H CF₃ Hex-c Cl Me MeH H 2 H H Cl Hex-c CF₃ Me Me H H 2 H H Me CH₂Pr-c OCHF₂ Me Me H H 2 H HOCHF₂ CH₂Pr-c Me Me Me H H 2 H H Cl CH₂Pr-c Cl Me Me H H 2 H H OCHF₂CH₂Pr-c Cl Me Me H H 2 H H Cl CH₂Pr-c OCHF₂ Me Me H H 2 H H OCHF₂CH₂Pr-c OCHF₂ Me Me H H 2 H H CF₃ CH₂Pr-c F Me Me H H 2 H H F CH₂Pr-cCF₃ Me Me H H 2 H H CF₃ CH₂Pr-c Cl Me Me H H 2 H H Cl CH₂Pr-c CF₃ Me MeH H 2 H H CF₃ CH₂Pr-c OH Me Me H H 2 H H CF₃ CH₂Pr-c OMe Me Me H H 2 H HOMe CH₂Pr-c CF₃ Me Me H H 2 H H CF₃ CH₂Pr-c OEt Me Me H H 2 H H OEtCH₂Pr-c CF₃ Me Me H H 2 H H CF₃ CH₂Pr-c OPr-i Me Me H H 2 H H CF₃CH₂Pr-c OPr Me Me H H 2 H H CF₃ CH₂Pr-c OBu-t Me Me H H 2 H H CF₃CH₂Pr-c OCH₂Pr-c Me Me H H 2 H H CF₃ CH₂Pr-c OCH₂Bu-c Me Me H H 2 H HCF₃ CH₂Pr-c OPen-c Me Me H H 2 H H CF₃ CH₂Pr-c OCHF₂ Me Me H H 2 H HOCHF₂ CH₂Pr-c CF₃ Me Me H H 2 H H CF₃ CH₂Pr-c CN Me Me H H 2 H H CNCH₂Pr-c CF₃ Me Me H H 2 H H CF₃ CH₂Pr-c Me Me Me H H 2 H H Me CH₂Pr-cCF₃ Me Me H H 2 H H CF₃ 1-cyclopropylethyl Cl Me Me H H 2 H H Cl1-cyclopropylethyl CF₃ Me Me H H 2 H H CF₃ CH₂(2-Methyl-cyclopropyl) ClMe Me H H 2 H H Cl CH₂(2-Methyl-cyclopropyl) CF₃ Me Me H H 2 H H CF₃CH₂(2,2-Dimethyl-cyclopropyl) Cl Me Me H H 2 H H ClCH₂(2,2-Dimethyl-cyclopropyl) CF₃ Me Me H H 2 H H CF₃CH₂(2-Chloro-cyclopropyl) Cl Me Me H H 2 H H ClCH₂(2-Chloro-cyclopropyl) CF₃ Me Me H H 2 H H CF₃CH₂(2,2-Dichloro-cyclopropyl) Cl Me Me H H 2 H H ClCH₂(2,2-Dichloro-cyclopropyl) CF₃ Me Me H H 2 H H CF₃CH₂(2-Fluoro-cyclopropyl) Cl Me Me H H 2 H H ClCH₂(2-Fluoro-cyclopropyl) CF₃ Me Me H H 2 H H CF₃CH₂(2,2-Difluoro-cyclopropyl) Cl Me Me H H 2 H H ClCH₂(2,2-Difluoro-cyclopropyl) CF₃ Me Me H H 2 H H CF₃ CH₂Bu-c Cl Me Me HH 2 H H Cl CH₂Bu-c CF₃ Me Me H H 2 H H CF₃ CH₂Pen-c Cl Me Me H H 2 H HCl CH₂Pen-c CF₃ Me Me H H 2 H H CF₃ CH₂Hex-c Cl Me Me H H 2 H H ClCH₂Hex-c CF₃ Me Me H H 2 H H CF₃ CH₂CH₂Pr-c Cl Me Me H H 2 H H ClCH₂CH₂Pr-c CF₃ Me Me H H 2 H H CF₃ CH₂CH═CH₂ Cl Me Me H H 2 H H ClCH₂CH═CH₂ CF₃ Me Me H H 2 H H CF₃ CH₂CH═CHCl Cl Me Me H H 2 H H ClCH₂CH═CHCl CF₃ Me Me H H 2 H H Me CH₂C≡CH OCHF₂ Me Me H H 2 H H OCHF₂CH₂C═CH Me Me Me H H 2 H H Cl CH₂CCH Cl Me Me H H 2 H H OCHF₂ CH₂C≡CH ClMe Me H H 2 H H Cl CH₂C≡CH OCHF₂ Me Me H H 2 H H OCHF₂ CH₂C≡CH OCHF₂ MeMe H H 2 H H CF₃ CH₂C≡CH F Me Me H H 2 H H F CH₂C≡CH CF₃ Me Me H H 2 H HCF₃ CH₂C≡CH Cl Me Me H H 2 H H Cl CH₂C≡CH CF₃ Me Me H H 2 H H CF₃CH₂C≡CH OMe Me Me H H 2 H H OMe CH₂C≡CH CF₃ Me Me H H 2 H H CF₃ CH₂C≡CHOEt Me Me H H 2 H H OEt CH₂C≡CH CF₃ Me Me H H 2 H H CF₃ CH₂C≡CH OCHF₂ MeMe H H 2 H H OCHF₂ CH₂C≡CH CF₃ Me Me H H 2 H H CF₃ CH₂C≡CH CN Me Me H H2 H H CN CH₂C≡CH CF₃ Me Me H H 2 H H CF₃ CH₂C≡CH Me Me Me H H 2 H H MeCH₂C≡CH CF₃ Me Me H H 2 H H CF₃ CHMeC≡CH Cl Me Me H H 2 H H Cl CHMeC≡CHCF₃ Me Me H H 2 H H CF₃ CH₂C≡CMe Cl Me Me H H 2 H H Cl CH₂C≡CMe CF₃ MeMe H H 2 H H Me CHF₂ F Me Me H H 2 H H F CHF₂ Me Me Me H H 2 H H Me CHF₂Cl Me Me H H 2 H H Cl CHF₂ Me Me Me H H 2 H H Me CHF₂ OMe Me Me H H 2 HH OMe CHF₂ Me Me Me H H 2 H H Me CHF₂ OCHF₂ Me Me H H 2 H H OCHF₂ CHF₂Me Me Me H H 2 H H Me CHF₂ CN Me Me H H 2 H H CN CHF₂ Me Me Me H H 2 H HMe CHF₂ Me Me Me H H 2 H H Et CHF₂ Cl Me Me H H 2 H H Cl CHF₂ Et Me Me HH 2 H H Et CHF₂ Et Me Me H H 2 H H Pr-i CHF₂ Cl Me Me H H 2 H H Cl CHF₂Pr-i Me Me H H 2 H H Cl CHF₂ Cl Me Me H H 2 H H OCHF₂ CHF₂ Cl Me Me H H2 H H Cl CHF₂ OCHF₂ Me Me H H 2 H H OCHF₂ CHF₂ OCHF₂ Me Me H H 2 H H CF₃CHF₂ Cl Me Me H H 2 H H Cl CHF₂ CF₃ Me Me H H 2 H H CF₃ CHF₂ F Me Me H H2 H H F CHF₂ CF₃ Me Me H H 2 H H CF₃ CHF₂ OMe Me Me H H 2 H H OMe CHF₂CF₃ Me Me H H 2 H H CF₃ CHF₂ OEt Me Me H H 2 H H OEt CHF₂ CF₃ Me Me H H2 H H CF₃ CHF₂ OCHF₂ Me Me H H 2 H H OCHF₂ CHF₂ CF₃ Me Me H H 2 H H CF₃CHF₂ CN Me Me H H 2 H H CN CHF₂ CF₃ Me Me H H 2 H H CF₃ CHF₂ Me Me Me HH 2 H H Me CHF₂ CF₃ Me Me H H 2 H H CF₃ CH₂CHF₂ Cl Me Me H H 2 H H ClCH₂CHF₂ CF₃ Me Me H H 2 H H CF₃ CH₂CF₃ Cl Me Me H H 2 H H Cl CH₂CF₃ CF₃Me Me H H 2 H H CF₃ CH₂OH Cl Me Me H H 2 H H Cl CH₂OH CF₃ Me Me H H 2 HH Me CH₂OMe OCHF₂ Me Me H H 2 H H OCHF₂ CH₂OMe Me Me Me H H 2 H H ClCH₂OMe Cl Me Me H H 2 H H OCHF₂ CH₂OMe Cl Me Me H H 2 H H Cl CH₂OMeOCHF₂ Me Me H H 2 H H OCHF₂ CH₂OMe OCHF₂ Me Me H H 2 H H CF₃ CH₂OMe F MeMe H H 2 H H F CH₂OMe CF₃ Me Me H H 2 H H CF₃ CH₂OMe Cl Me Me H H 2 H HCl CH₂OMe CF₃ Me Me H H 2 H H CF₃ CH₂OMe OMe Me Me H H 2 H H OMe CH₂OMeCF₃ Me Me H H 2 H H CF₃ CH₂OMe OEt Me Me H H 2 H H OEt CH₂OMe CF₃ Me MeH H 2 H H CF₃ CH₂OMe OCHF₂ Me Me H H 2 H H OCHF₂ CH₂OMe CF₃ Me Me H H 2H H CF₃ CH₂OMe CN Me Me H H 2 H H CN CH₂OMe CF₃ Me Me H H 2 H H CF₃CH₂OMe Me Me Me H H 2 H H Me CH₂OMe CF₃ Me Me H H 2 H H CF₃ CH₂OEt Cl MeMe H H 2 H H Cl CH₂OEt CF₃ Me Me H H 2 H H CF₃ CH₂CH₂OH Cl Me Me H H 2 HH Cl CH₂CH₂OH CF₃ Me Me H H 2 H H CF₃ CH₂CH₂OMe Cl Me Me H H 2 H H ClCH₂CH₂OMe CF₃ Me Me H H 2 H H CF₃ CH₂CH₂OEt Cl Me Me H H 2 H H ClCH₂CH₂OEt CF₃ Me Me H H 2 H H CF₃ CH₂NHMe Cl Me Me H H 2 H H Cl CH₂NHMeCF₃ Me Me H H 2 H H CF₃ CH₂N(Me)₂ Cl Me Me H H 2 H H Cl CH₂N(Me)₂ CF₃ MeMe H H 2 H H CF₃ CH₂N(Me)C(═O)Me Cl Me Me H H 2 H H Cl CH₂N(Me)C(═O)MeCF₃ Me Me H H 2 H H CF₃ CH₂N(Me)C(═O)CF₃ Cl Me Me H H 2 H H ClCH₂N(Me)C(═O)CF₃ Me Me H H 2 H H CF₃ CH₂N(Me)SO₂Me Cl Me Me H H 2 H H ClCH₂N(Me)SO₂Me CF₃ Me Me H H 2 H H CF₃ CH₂N(Me)SO₂CHF₂ Cl Me Me H H 2 H HCl CH₂N(Me)SO₂CHF₂ CF₃ Me Me H H 2 H H CF₃ CH₂N(Me)SO₂CF₃ Cl Me Me H H 2H H Cl CH₂N(Me)SO₂CF₃ CF₃ Me Me H H 2 H H CF₃ CH₂SMe Cl Me Me H H 2 H HCl CH₂SMe CF₃ Me Me H H 2 H H CF₃ CH₂SO₂Me Cl Me Me H H 2 H H ClCH₂SO₂Me CF₃ Me Me H H 2 H H CF₃ CH₂CH₂SMe Cl Me Me H H 2 H H ClCH₂CH₂SMe CF₃ Me Me H H 2 H H CF₃ CH₂CH₂SO₂Me Cl Me Me H H 2 H H ClCH₂CH₂SO₂Me CF₃ Me Me H H 2 H H CF₃ CH₂CN Cl Me Me H H 2 H H Cl CH₂CNCF₃ Me Me H H 2 H H CF₃ CH₂C(═O)OMe Cl Me Me H H 2 H H Cl CH₂C(═O)OMeCF₃ Me Me H H 2 H H CF₃ CH₂C(═O)OEt Cl Me Me H H 2 H H Cl CH₂C(═O)OEtCF₃ Me Me H H 2 H H CF₃ CH(Me)C(═O)OMe Cl Me Me H H 2 H H ClCH(Me)C(═O)OMe CF₃ Me Me H H 2 H H CF₃ C(Me)₂C(═O)OMe Cl Me Me H H 2 H HCl C(Me)₂C(═O)OMe CF₃ Me Me H H 2 H H CF₃ CH₂C(═O)NH₂ Cl Me Me H H 2 H HCl CH₂C(═O)NH₂ CF₃ Me Me H H 2 H H CF₃ CH₂C(═O)NHMe Cl Me Me H H 2 H HCl CH₂C(═O)NHMe CF₃ Me Me H H 2 H H CF₃ CH₂C(═O)N(Me)₂ Cl Me Me H H 2 HH Cl CH₂C(═O)N(Me)₂ CF₃ Me Me H H 2 H H CF₃ CH₂C(═O)Me Cl Me Me H H 2 HH Cl CH₂C(═O)Me CF₃ Me Me H H 2 H H CF₃ CH₂C(═NOMe)Me Cl Me Me H H 2 H HCl CH₂C(═NOMe)Me CF₃ Me Me H H 2 H H CF₃ CH₂C(═O)CF₃ Cl Me Me H H 2 H HCl CH₂C(═O)CF₃ CF₃ Me Me H H 2 H H CF₃ CH₂CH₂C(═O)Me Cl Me Me H H 2 H HCl CH₂CH₂C(═O)Me CF₃ Me Me H H 2 H H Me Ph Me Me Me H H 2 H H Me Ph F MeMe H H 2 H H Me Ph Cl Me Me H H 2 H H Me Ph OCHF₂ Me Me H H 2 H H Me PhCN Me Me H H 2 H H Et Ph F Me Me H H 2 H H Et Ph Cl Me Me H H 2 H H EtPh OCHF₂ Me Me H H 2 H H Et Ph CN Me Me H H 2 H H Pr Ph F Me Me H H 2 HH Pr Ph Cl Me Me H H 2 H H Pr Ph OCHF₂ Me Me H H 2 H H Pr Ph CN Me Me HH 2 H H Pr-i Ph F Me Me H H 2 H H Pr-i Ph Cl Me Me H H 2 H H Pr-i PhOCHF₂ Me Me H H 2 H H Pr-i Ph CN Me Me H H 2 H H Bu-t Ph Cl Me Me H H 2H H CH₂OMe Ph Cl Me Me H H 2 H H Cl Ph Cl Me Me H H 2 H H OCHF₂ Ph Cl MeMe H H 2 H H OCHF₂ Ph OCHF₂ Me Me H H 2 H H CHF₂ Ph Cl Me Me H H 2 H HCF₃ Ph H Me Me H H 2 H H CF₃ Ph Me Me Me H H 2 H H Me Ph CF₃ Me Me H H 2H H CF₃ Ph Et Me Me H H 2 H H CF₃ Ph Pr-i Me Me H H 2 H H CF₃ Ph CHF₂ MeMe H H 2 H H CF₃ Ph CF₃ Me Me H H 2 H H CF₃ Ph F Me Me H H 2 H H CF₃ PhCl Me Me H H 2 H H Cl Ph CF₃ Me Me H H 2 H H CF₃ Ph OH Me Me H H 2 H HOH Ph CF₃ Me Me H H 2 H H CF₃ Ph OMe Me Me H H 2 H H OMe Ph CF₃ Me Me HH 2 H H CF₃ Ph OEt Me Me H H 2 H H OEt Ph CF₃ Me Me H H 2 H H CF₃ PhOPr-i Me Me H H 2 H H CF₃ Ph OPr Me Me H H 2 H H CF₃ Ph OBu-t Me Me H H2 H H CF₃ Ph OCH₂Pr-c Me Me H H 2 H H CF₃ Ph OCH₂CH═CH₂ Me Me H H 2 H HCF₃ Ph OCH₂C≡CH Me Me H H 2 H H CF₃ Ph OCHF₂ Me Me H H 2 H H OCHF₂ PhCF₃ Me Me H H 2 H H CF₃ Ph OCH₂CHF₂ Me Me H H 2 H H CF₃ Ph OCH₂CF₃ Me MeH H 2 H H CF₃ Ph OCH₂C(═O)OMe Me Me H H 2 H H CF₃ Ph OCH(Me)C(═O)OMe MeMe H H 2 H H CF₃ Ph OC(Me)₂C(═O)OMe Me Me H H 2 H H CF₃ Ph OC(═O)Me MeMe H H 2 H H CF₃ Ph OC(═O)Et Me Me H H 2 H H CF₃ Ph OC(═O)CH₂Ph Me Me HH 2 H H CF₃ Ph OC(═O)CF₃ Me Me H H 2 H H CF₃ Ph OC(═O)Ph Me Me H H 2 H HCF₃ Ph OSO₂Me Me Me H H 2 H H CF₃ Ph OSO₂Et Me Me H H 2 H H CF₃ PhOSO₂CH₂Ph Me Me H H 2 H H CF₃ Ph OSO₂CF₃ Me Me H H 2 H H CF₃ Ph OSO₂PhMe Me H H 2 H H CF₃ Ph SMe Me Me H H 2 H H CF₃ Ph SOMe Me Me H H 2 H HCF₃ Ph SO₂Me Me Me H H 2 H H CF₃ Ph SEt Me Me H H 2 H H CF₃ Ph SOEt MeMe H H 2 H H CF₃ Ph SO₂Et Me Me H H 2 H H CF₃ Ph SPr-i Me Me H H 2 H HCF₃ Ph SOPr-i Me Me H H 2 H H CF₃ Ph SO₂Pr-i Me Me H H 2 H H CF₃ Ph SPrMe Me H H 2 H H CF₃ Ph SOPr Me Me H H 2 H H CF₃ Ph SO₂Pr Me Me H H 2 H HCF₃ Ph SBu-t Me Me H H 2 H H CF₃ Ph SOBu-t Me Me H H 2 H H CF₃ PhSO₂Bu-t Me Me H H 2 H H CF₃ Ph SCHF₂ Me Me H H 2 H H CF₃ Ph SOCHF₂ Me MeH H 2 H H CF₃ Ph SO₂CHF₂ Me Me H H 2 H H CF₃ Ph NH₂ Me Me H H 2 H H CF₃Ph NHMe Me Me H H 2 H H CF₃ Ph N(Me)₂ Me Me H H 2 H H CF₃ Ph NHC(═O)MeMe Me H H 2 H H CF₃ Ph N(Me)C(═O)Me Me Me H H 2 H H CF₃ Ph NHSO₂Me Me MeH H 2 H H CF₃ Ph N(Me)SO₂Me Me Me H H 2 H H CF₃ Ph NHSO₂CF₃ Me Me H H 2H H CF₃ Ph N(Me)SO₂CF₃ Me Me H H 2 H H CF₃ Ph NHPh Me Me H H 2 H H CF₃Ph N(Me)Ph Me Me H H 2 H H CF₃ Ph CN Me Me H H 2 H H CF₃ Ph C(═O)Me MeMe H H 2 H H CF₃ Ph C(═O)OMe Me Me H H 2 H H CF₃ Ph C(═O)NH₂ Me Me H H 2H H CF₃ Ph C(═O)NHMe Me Me H H 2 H H CF₃ Ph C(═O)N(Me)₂ Me Me H H 2 H HCF₃ Ph Imidazol-1-yl Me Me H H 2 H H CF₃ Ph Pyrazol-1-yl Me Me H H 2 H HCF₃ Ph 1,2,4-Triazol-1-yl Me Me H H 2 H H CF₃ Ph 1,2,4-Triazol-4-yI MeMe H H 2 H H CF₃ Ph Tetrazol-1-yl Me Me H H 2 H H CF₃ Ph Tetrazol-5-ylMe Me H H 2 H H CF₃ Ph (4,6-Dimethoxypyrimidin-2-yl)oxy Me Me H H 2 H HCF₃ Ph (4,6-Dimethoxypyrimidin-2-yl) sulfonyl Me Me H H 2 H H CF₂CF₃ PhCl Me Me H H 2 H H CF₃ (2-Cl)Ph Cl Me Me H H 2 H H CF₃ (2-F)Ph Cl Me MeH H 2 H H CF₃ (2-OMe)Ph Cl Me Me H H 2 H H CF₃ (2-Me)Ph Cl Me Me H H 2 HH CF₃ (2-NO₂)Ph Cl Me Me H H 2 H H CF₃ (2-CN)Ph Cl Me Me H H 2 H H CF₃(2-C(═O)Me)Ph Cl Me Me H H 2 H H CF₃ (2-C(═O)OMe)Ph Cl Me Me H H 2 H HCF₃ (2-C(═O)OEt)Ph Cl Me Me H H 2 H H CF₃ (2-C(═O)OPr-i)Ph Cl Me Me H H2 H H CF₃ (2-C(═O)NH₂)Ph Cl Me Me H H 2 H H CF₃ (2-C(═O)NHMe)Ph Cl Me MeH H 2 H H CF₃ (2-C(═O)NMe₂)Ph Cl Me Me H H 2 H H CF₃ (3-Cl)Ph Cl Me Me HH 2 H H CF₃ (3-F)Ph Cl Me Me H H 2 H H CF₃ (3-OMe)Ph Cl Me Me H H 2 H HCF₃ (3-Me)Ph Cl Me Me H H 2 H H CF₃ (3-NO₂)Ph Cl Me Me H H 2 H H CF₃(3-CN)Ph Cl Me Me H H 2 H H CF₃ (3-C(═O)Me)Ph Cl Me Me H H 2 H H CF₃(3-C(═O)OMe)Ph Cl Me Me H H 2 H H CF₃ (3-C(═)OEt)Ph Cl Me Me H H 2 H HCF₃ (3-C(═O)OPr-i)Ph Cl Me Me H H 2 H H CF₃ (3-C(═O)NH₂)Ph Cl Me Me H H2 H H CF₃ (3-C(═O)NHMe)Ph Cl Me Me H H 2 H H CF₃ (3-C(═O)NMe₂)Ph Cl MeMe H H 2 H H CF₃ (4-Cl)Ph Cl Me Me H H 2 H H CF₃ (4-F)Ph Cl Me Me H H 2H H CF₃ (4-OMe)Ph Cl Me Me H H 2 H H CF₃ (4-Me)Ph Cl Me Me H H 2 H H CF₃(4-NO₂)Ph Cl Me Me H H 2 H H CF₃ (4-CN)Ph Cl Me Me H H 2 H H CF₃(4-C(═O)MePh Cl Me Me H H 2 H H CF₃ (4-C(═O)OMe)Ph Cl Me Me H H 2 H HCF₃ (4-C(═O)OEt)Ph Cl Me Me H H 2 H H CF₃ (4-C(═O)OPr-i)Ph Cl Me Me H H2 H H CF₃ (4-C(═O)NH₂)Ph Cl Me Me H H 2 H H CF₃ (4-C(═O)NHMe)Ph Cl Me MeH H 2 H H CF₃ (4-C(═O)NMe₂)Ph Cl Me Me H H 2 H H CF₃ Pyrmidin-2-yl Cl MeMe H H 2 H H CF₃ 4,6-Dimethoxypyrmidin-2-yl Cl Me Me H H 2 H H CF₃Thiophen-2-yl Cl Me Me H H 2 H H CF₃ Furan-2-yl Cl Me Me H H 2 H H CF₃SO₂Me Cl Me Me H H 2 H H CF₃ SO₂Et Cl Me Me H H 2 H H CF₃ SO₂Pr-i Cl MeMe H H 2 H H CF₃ SO₂CH₂Ph Cl Me Me H H 2 H H CF₃ SO₂CHF₂ Cl Me Me H H 2H H CF₃ SO₂CF₃ Cl Me Me H H 2 H H CF₃ SO₂Ph Cl Me Me H H 2 H H CF₃C(═O)Me Cl Me Me H H 2 H H CF₃ C(═O)Et Cl Me Me H H 2 H H CF₃ C(═O)Pr-iCl Me Me H H 2 H H CF₃ C(═O)Bu-t Cl Me Me H H 2 H H CF₃ C(═O)Ph Cl Me MeH H 2 H H CF₃ C(═O)CH₂Ph Cl Me Me H H 2 H H CF₃ C(═O)CH₂Cl Cl Me Me H H2 H H CF₃ C(═O)CHCl₂ Cl Me Me H H 2 H H CF₃ C(═O)CF₃ Cl Me Me H H 2 H HCF₃ C(═O)OMe Cl Me Me H H 2 H H CF₃ C(═O)OPh Cl Me Me H H 2 H H CF₃C(═O)OCH₂Ph Cl Me Me H H 2 H H CF₃ C(═O)NHMe Cl Me Me H H 2 H H CF₃C(═O)N(Me)₂ Cl Me Me H H 2 H H CF₃ C(═O)NHPh Cl Me Me H H 2 H H CF₃ NH₂Cl Me Me H H 2 H H Cl —(CH₂)₂O— Me Me H H 2 H H Cl —(CH₂)₃O— Me Me H H 2H H Cl —(CH₂)₃S— Me Me H H 2 H H Cl —(CH₂)₃SO₂— Me Me H H 2 H H CF₃—(CH₂)₂O— Me Me H H 2 H H CF₃ —(CH₂)₃O— Me Me H H 2 H H CF₃ —(CH₂)₃S— MeMe H H 2 H H CF₃ —(CH₂)₃SO₂— Me Me H H 2 H H OMe —(CH₂)₄— Me Me H H 2 HH OCHF₂ —(CH₂)₄— H H H H 2 H H CF₃ Me Cl Me H H H 2 H H CF₃ Me Cl Me HMe H 2 H H CF₃ Me Cl Me Me Me H 2 H H CF₃ Me Cl Me Me H H 2 Me H CF₃ MeCl Me Me H H 2 Et H CF₃ Me Cl Me Me H H 2 Pr-i H CF₃ Me Cl Me Me H H 2Me Me CF₃ Me Cl Me Et H H 2 H H CF₃ Me Cl Et Et H H 2 H H CF₃ Me Cl MePr-i H H 2 H H CF₃ Me Cl Me Pr H H 2 H H CF₃ Me Cl Me Pr-c H H 2 H H CF₃Me Cl Me CH₂Pr-c H H 2 H H CF₃ Me Cl —(CH₂)₂— H H 2 H H CF₃ Me Cl—(CH₂)₃— H H 2 H H CF₃ Me Cl —(CH₂)₄— H H 2 H H CF₃ Me Cl —(CH₂)₅— H H 2H H CF₃ Me Cl H —(CH₂)₃— H 2 H H CF₃ Me Cl H —(CH₂)₄— H 2 H H CF₃ Me ClH —(CH₂)₅— H 2 H H CF₃ Me Cl H —(CH₂)₆— H 2 H H CF₃ Me Cl Me Me H H 1 HH Cl H Cl Me Me H H 1 H H OCHF₂ H Cl Me Me H H 1 H H OCHF₂ H OCHF₂ Me MeH H 1 H H CHF₂ H Cl Me Me H H 1 H H CF₃ H F Me Me H H 1 H H CF₃ H Cl MeMe H H 1 H H CF₃ H OMe Me Me H H 1 H H CF₃ H OEt Me Me H H 1 H H CF₃ HOCHF₂ Me Me H H 1 H H CF₃ H CN Me Me H H 1 H H CF₃ H Me Me Me H H 1 H HH Me Cl Me Me H H 1 H H Me Me Me Me Me H H 1 H H Me Me Cl Me Me H H 1 HH Cl Me Me Me Me H H 1 H H Et Me Cl Me Me H H 1 H H Cl Me Et Me Me H H 1H H Pr-i Me Cl Me Me H H 1 H H Cl Me Pr-i Me Me H H 1 H H Bu-t Me Cl MeMe H H 1 H H Cl Me Bu-t Me Me H H 1 H H Cl Me Cl Me Me H H 1 H H CHF₂ MeCl Me Me H H 1 H H Cl Me CHF₂ Me Me H H 1 H H OCHF₂ Me H Me Me H H 1 H HOCHF₂ Me Cl Me Me H H 1 H H Cl Me OCHF₂ Me Me H H 1 H H OCHF₂ Me OCHF₂Me Me H H 1 H H CF₃ Me H Me Me H H 1 H H CF₃ Me Cl Me Me H H 1 H H Cl MeCF₃ Me Me H H 1 H H CF₃ Me F Me Me H H 1 H H F Me CF₃ Me Me H H 1 H HCF₃ Me OH Me Me H H 1 H H OH Me CF₃ Me Me H H 1 H H CF₃ Me OMe Me Me H H1 H H OMe Me CF₃ Me Me H H 1 H H CF₃ Me OEt Me Me H H 1 H H OEt Me CF₃Me Me H H 1 H H CF₃ Me OPr-i Me Me H H 1 H H CF₃ Me OPr Me Me H H 1 H HCF₃ Me OBu-t Me Me H H 1 H H CF₃ Me OBu-s Me Me H H 1 H H CF₃ Me OBu-iMe Me H H 1 H H CF₃ Me OBu Me Me H H 1 H H CF₃ Me O(2-Pen) Me Me H H 1 HH CF₃ Me O(3-Pen) Me Me H H 1 H H CF₃ Me OPen-n Me Me H H 1 H H CF₃ MeO(2-Hex) Me Me H H 1 H H CF₃ Me O(3-Hex) Me Me H H 1 H H CF₃ Me OHex-nMe Me H H 1 H H CF₃ Me OPen-c Me Me H H 1 H H CF₃ Me OHex-c Me Me H H 1H H CF₃ Me OCH₂Pr-c Me Me H H 1 H H CF₃ Me OCH₂Bu-c Me Me H H 1 H H CF₃Me OCH₂Pen-c Me Me H H 1 H H CF₃ Me OCH₂Hex-c Me Me H H 1 H H CF₃ MeOCH₂CH═CH₂ Me Me H H 1 H H CF₃ Me OCH₂C≡CH Me Me H H 1 H H CF₃ Me OCHF₂Me Me H H 1 H H OCHF₂ Me CF₃ Me Me H H 1 H H CF₃ Me OCH₂CHF₂ Me Me H H 1H H OCH₂CHF₂ Me CF₃ Me Me H H 1 H H CF₃ Me OCH₂CF₃ Me Me H H 1 H HOCH₂CF₃ Me CF₃ Me Me H H 1 H H CF₃ Me OCH₂CN Me Me H H 1 H H CF₃ MeOCH₂C(═O)OEt Me Me H H 1 H H CF₃ Me OCH(Me)C(═O)OEt Me Me H H 1 H H CF₃Me OCH₂C(═O)NH₂ Me Me H H 1 H H CF₃ Me OCH₂C(═O)NHMe Me Me H H 1 H H CF₃Me OCH₂C(═O)N(Me)₂ Me Me H H 1 H H CF₃ Me OCH₂Ph Me Me H H 1 H H CF₃ MeOPh Me Me H H 1 H H CF₃ Me O(2-Cl)Ph Me Me H H 1 H H CF₃ Me O(2-Br)Ph MeMe H H 1 H H CF₃ Me O(2-F)Ph Me Me H H 1 H H CF₃ Me O(2-Me)Ph Me Me H H1 H H CF₃ Me O(2-OMe)Ph Me Me H H 1 H H CF₃ Me O(2-NO₂)Ph Me Me H H 1 HH CF₃ Me O(2-CN)Ph Me Me H H 1 H H CF₃ Me O(2-C(═O)OMe)Ph Me Me H H 1 HH CF₃ Me O(3-Cl)Ph Me Me H H 1 H H CF₃ Me O(3-Br)Ph Me Me H H 1 H H CF₃Me O(3-F)Ph Me Me H H 1 H H CF₃ Me O(3-Me)Ph Me Me H H 1 H H CF₃ MeO(3-OMe)Ph Me Me H H 1 H H CF₃ Me O(3-NO₂)Ph Me Me H H 1 H H CF₃ MeO(3-CN)Ph Me Me H H 1 H H CF₃ Me O(3-C(═O)OMe)Ph Me Me H H 1 H H CF₃ MeO(4-Cl)Ph Me Me H H 1 H H CF₃ Me O(4-Br)Ph Me Me H H 1 H H CF₃ MeO(4-F)Ph Me Me H H 1 H H CF₃ Me O(4-Me)Ph Me Me H H 1 H H CF₃ MeO(4-OMe)Ph Me Me H H 1 H H CF₃ Me O(4-NO₂)Ph Me Me H H 1 H H CF₃ MeO(4-CN)Ph Me Me H H 1 H H CF₃ Me O(4-C(═O)OMe)Ph Me Me H H 1 H H CF₃ MeOC(═O)Me Me Me H H 1 H H CF₃ Me OC(═O)Et Me Me H H 1 H H CF₃ MeOC(═O)CH₂Ph Me Me H H 1 H H CF₃ Me OC(═O)CF₃ Me Me H H 1 H H CF₃ MeOC(═O)Ph Me Me H H 1 H H CF₃ Me OSO₂Me Me Me H H 1 H H CF₃ Me OSO₂Et MeMe H H 1 H H CF₃ Me OSO₂CH₂Ph Me Me H H 1 H H CF₃ Me OSO₂CF₃ Me Me H H 1H H CF₃ Me OSO₂Ph Me Me H H 1 H H CF₃ Me SMe Me Me H H 1 H H CF₃ MeSO₂Me Me Me H H 1 H H CF₃ Me SEt Me Me H H 1 H H CF₃ Me SO₂Et Me Me H H1 H H CF₃ Me SPr Me Me H H 1 H H CF₃ Me SO₂Pr Me Me H H 1 H H CF₃ MeSPr-i Me Me H H 1 H H CF₃ Me SO₂Pr-i Me Me H H 1 H H CF₃ Me SBu-t Me MeH H 1 H H CF₃ Me SO₂Bu-t Me Me H H 1 H H CF₃ Me SCHF₂ Me Me H H 1 H HCF₃ Me SO₂CHF₂ Me Me H H 1 H H CF₃ Me SCF₃ Me Me H H 1 H H CF₃ Me SO₂CF₃Me Me H H 1 H H CF₃ Me SPh Me Me H H 1 H H CF₃ Me SO₂Ph Me Me H H 1 H HCF₃ Me SCH₂Ph Me Me H H 1 H H CF₃ Me SO₂CH₂Ph Me Me H H 1 H H CF₃ MeSCH₂C(═O)OEt Me Me H H 1 H H CF₃ Me SO₂CH₂C(═O)OEt Me Me H H 1 H H CF₃Me SCH(Me)C(═O)OEt Me Me H H 1 H H CF₃ Me SO₂CH(Me)C(═O)OEt Me Me H H 1H H CF₃ Me SCH₂C(═O)NH₂ Me Me H H 1 H H CF₃ Me SO₂CH₂C(═O)NH₂ Me Me H H1 H H CF₃ Me SCH₂C(═O)NHMe Me Me H H 1 H H CF₃ Me SO₂CH₂C(═O)NHMe Me MeH H 1 H H CF₃ Me SCH₂C(═O)N(Me)₂ Me Me H H 1 H H CF₃ MeSO₂CH₂C(═O)N(Me)₂ Me Me H H 1 H H CF₃ Me NH₂ Me Me H H 1 H H CF₃ Me NHMeMe Me H H 1 H H CF₃ Me N(Me)₂ Me Me H H 1 H H CF₃ Me NHC(═O)Me Me Me H H1 H H CF₃ Me N(Me)C(═O)Me Me Me H H 1 H H CF₃ Me NHSO₂Me Me Me H H 1 H HCF₃ Me N(Me)SO₂Me Me Me H H 1 H H CF₃ Me NHSO₂CHF₂ Me Me H H 1 H H CF₃Me N(Me)SO₂CHF₂ Me Me H H 1 H H CF₃ Me NHSO₂CF₃ Me Me H H 1 H H CF₃ MeN(Me)SO₂CF₃ Me Me H H 1 H H CF₃ Me NHPh Me Me H H 1 H H CF₃ Me N(Me)PhMe Me H H 1 H H CF₃ Me CN Me Me H H 1 H H CN Me CF₃ Me Me H H 1 H H CF₃Me C(═O)OMe Me Me H H 1 H H CF₃ Me C(═O)OCH₂Ph Me Me H H 1 H H CF₃ MeC(═O)OPh Me Me H H 1 H H CF₃ Me C(═O)NH₂ Me Me H H 1 H H CF₃ MeC(═O)NHMe Me Me H H 1 H H CF₃ Me C(═O)N(Me)₂ Me Me H H 1 H H CF₃ MeC(═O)Me Me Me H H 1 H H CF₃ Me C(═O)CF₃ Me Me H H 1 H H CF₃ MeC(═O)CH₂ph Me Me H H 1 H H CF₃ Me C(═O)Ph Me Me H H 1 H H CF₃ Me Me MeMe H H 1 H H Me Me CF₃ Me Me H H 1 H H CF₃ Me Et Me Me H H 1 H H CF₃ MePr-i Me Me H H 1 H H CF₃ Me Pr Me Me H H 1 H H CF₃ Me CH₂OMe Me Me H H 1H H CF₃ Me CF₃ Me Me H H 1 H H CF₃ Me CHF₂ Me Me H H 1 H H CF₃ Me Ph MeMe H H 1 H H CF₂CF₃ Me Cl Me Me H H 1 H H Ph Me Me Me Me H H 1 H H Ph MeCl Me Me H H 1 H H Ph Me OEt Me Me H H 1 H H Ph Me CF₃ Me Me H H 1 H HPh Me Ph Me Me H H 1 H H Cl Et Cl Me Me H H 1 H H OCHF₂ Et Cl Me Me H H1 H H Cl Et OCHF₂ Me Me H H 1 H H OCHF₂ Et OCHF₂ Me Me H H 1 H H CF₃ EtF Me Me H H 1 H H F Et CF₃ Me Me H H 1 H H CF₃ Et Cl Me Me H H 1 H H ClEt CF₃ Me Me H H 1 H H CF₃ Et OMe Me Me H H 1 H H OMe Et CF₃ Me Me H H 1H H CF₃ Et OEt Me Me H H 1 H H OEt Et CF₃ Me Me H H 1 H H CF₃ Et OCHF₂Me Me H H 1 H H OCHF₂ Et CF₃ Me Me H H 1 H H CF₃ Et CN Me Me H H 1 H HCN Et CF₃ Me Me H H 1 H H CF₃ Et Me Me Me H H 1 H H Me Et CF₃ Me Me H H1 H H Cl Pr-i Cl Me Me H H 1 H H OCHF₂ Pr-i Cl Me Me H H 1 H H Cl Pr-iOCHF₂ Me Me H H 1 H H OCHF₂ Pr-i OCHF₂ Me Me H H 1 H H CF₃ Pr-i F Me MeH H 1 H H F Pr-i CF₃ Me Me H H 1 H H CF₃ Pr-i Cl Me Me H H 1 H H Cl Pr-iCF₃ Me Me H H 1 H H CF₃ Pr-i OMe Me Me H H 1 H H OMe Pr-i CF₃ Me Me H H1 H H CF₃ Pr-i OEt Me Me H H 1 H H OEt Pr-i CF₃ Me Me H H 1 H H CF₃ Pr-iOCHF₂ Me Me H H 1 H H OCHF₂ Pr-i CF₃ Me Me H H 1 H H CF₃ Pr-i CN Me Me HH 1 H H CN Pr-i CF₃ Me Me H H 1 H H CF₃ Pr-i Me Me Me H H 1 H H Me Pr-iCF₃ Me Me H H 1 H H Cl Pr Cl Me Me H H 1 H H OCHF₂ Pr Cl Me Me H H 1 H HCl Pr OCHF₂ Me Me H H 1 H H OCHF₂ Pr OCHF₂ Me Me H H 1 H H CF₃ Pr F MeMe H H 1 H H F Pr CF₃ Me Me H H 1 H H CF₃ Pr Cl Me Me H H 1 H H Cl PrCF₃ Me Me H H 1 H H CF₃ Pr OMe Me Me H H 1 H H OMe Pr CF₃ Me Me H H 1 HH CF₃ Pr OEt Me Me H H 1 H H OEt Pr CF₃ Me Me H H 1 H H CF₃ Pr OCHF₂ MeMe H H 1 H H OCHF₂ Pr CF₃ Me Me H H 1 H H CF₃ Pr CN Me Me H H 1 H H CNPr CF₃ Me Me H H 1 H H CF₃ Pr Me Me Me H H 1 H H Me Pr CF₃ Me Me H H 1 HH Cl Bu-t Cl Me Me H H 1 H H OCHF₂ Bu-t Cl Me Me H H 1 H H OCHF₂ Bu-tOCHF₂ Me Me H H 1 H H CF₃ Bu-t H Me Me H H 1 H H CF₃ Bu-t F Me Me H H 1H H CF₃ Bu-t Cl Me Me H H 1 H H Cl Bu-t CF₃ Me Me H H 1 H H CF₃ Bu-t OMeMe Me H H 1 H H OMe Bu-t CF₃ Me Me H H 1 H H CF₃ Bu-t OEt Me Me H H 1 HH OEt Bu-t CF₃ Me Me H H 1 H H CF₃ Bu-t OCHF₂ Me Me H H 1 H H CF₃ Bu-tCN Me Me H H 1 H H CF₃ Bu-t Me Me Me H H 1 H H Me Bu-t CF₃ Me Me H H 1 HH CF₃ Bu-s Cl Me Me H H 1 H H Cl Bu-s CF₃ Me Me H H 1 H H CF₃ Bu-i Cl MeMe H H 1 H H Cl Bu-i CF₃ Me Me H H 1 H H CF₃ Bu Cl Me Me H H 1 H H Cl BuCF₃ Me Me H H 1 H H CF₃ 1-Methylbutyl Cl Me Me H H 1 H H Cl1-Methylbutyl CF₃ Me Me H H 1 H H CF₃ 1-Ethylpropyl Cl Me Me H H 1 H HCl 1-Ethylpropyl CF₃ Me Me H H 1 H H CF₃ 1-Pentyl Cl Me Me H H 1 H H Cl1-Pentyl CF₃ Me Me H H 1 H H CF₃ 1-Methylpentyl Cl Me Me H H 1 H H Cl1-Methylpentyl CF₃ Me Me H H 1 H H CF₃ 2-Ethylbutyl Cl Me Me H H 1 H HCl 2-Ethylbutyl CF₃ Me Me H H 1 H H CF₃ 3,3-Dimethylbutyl Cl Me Me H H 1H H Cl 3,3-Diniethylbutyl CF₃ Me Me H H 1 H H CF₃ 1-Hexyl Cl Me Me H H 1H H Cl 1-Hexyl CF₃ Me Me H H 1 H H CF₃ 1-Heptyl Cl Me Me H H 1 H H Cl1-Heptyl CF₃ Me Me H H 1 H H CF₃ 1-Octyl Cl Me Me H H 1 H H Cl 1-OctylCF₃ Me Me H H 1 H H CF₃ CH₂Ph Cl Me Me H H 1 H H Cl CH₂Ph CF₃ Me Me H H1 H H CF₃ Pr-c Cl Me Me H H 1 H H CF₃ Pen-c Cl Me Me H H 1 H H Cl Pen-cCF₃ Me Me H H 1 H H CF₃ Hex-c Cl Me Me H H 1 H H Cl Hex-c CF₃ Me Me H H1 H H Cl CH₂Pr-c Cl Me Me H H 1 H H OCHF₂ CH₂Pr-c Cl Me Me H H 1 H H ClCH₂Pr-c OCHF₂ Me Me H H 1 H H OCHF₂ CH₂Pr-c OCHF₂ Me Me H H 1 H H CF₃CH₂Pr-c F Me Me H H 1 H H F CH₂Pr-c CF₃ Me Me H H 1 H H CF₃ CH₂Pr-c ClMe Me H H 1 H H Cl CH₂Pr-c CF₃ Me Me H H 1 H H CF₃ CH₂Pr-c CN Me Me H H1 H H CF₃ CH₂Pr-c OH Me Me H H 1 H H CF₃ CH₂Pr-c OMe Me Me H H 1 H H OMeCH₂Pr-c CF₃ Me Me H H 1 H H CF₃ CH₂Pr-c OEt Me Me H H 1 H H OEt CH₂Pr-cCF₃ Me Me H H 1 H H CF₃ CH₂Pr-c OPr-i Me Me H H 1 H H CF₃ CH₂Pr-c OPr MeMe H H 1 H H CF₃ CH₂Pr-c OBu-t Me Me H H 1 H H CF₃ CH₂Pr-c OCH₂Pr-c MeMe H H 1 H H CF₃ CH₂Pr-c OCH₂Bu-c Me Me H H 1 H H CF₃ CH₂Pr-c OPen-c MeMe H H 1 H H CF₃ CH₂Pr-c OCHF₂ Me Me H H 1 H H OCHF₂ CH₂Pr-c CF₃ Me Me HH 1 H H CF₃ CH₂Pr-c CN Me Me H H 1 H H CN CH₂Pr-c CF₃ Me Me H H 1 H HCF₃ CH₂Pr-c Me Me Me H H 1 H H Me CH₂Pr-c CF₃ Me Me H H I H H CF₃1-cyclopropylethyl Cl Me Me H H 1 H H Cl 1-cyclopropylethyl CF₃ Me Me HH 1 H H CF₃ CH₂(2-Methyl-cyclopropyl) Cl Me Me H H 1 H H ClCH₂(2-Methyl-cyclopropyl) CF₃ Me Me H H 1 H H CF₃CH₂(2,2-Dimethyl-cyclopropyl) Cl Me Me H H 1 H H ClCH₂(2,2-Dimethyl-cyclopropyl) CF₃ Me Me H H 1 H H CF₃CH₂(2-Chloro-cyclopropyl) Cl Me Me H H 1 H H ClCH₂(2-Chloro-cyclopropyl) CF₃ Me Me H H 1 H H CF₃CH₂(2,2-Dichloro-cyclopropyl) Cl Me Me H H 1 H H ClCH₂(2,2-Dichloro-cyclopropyl) CF₃ Me Me H H 1 H H CF₃CH₂(2-Fluoro-cyclopropyl) Cl Me Me H H 1 H H ClCH₂(2-Fluoro-cyclopropyl) CF₃ Me Me H H 1 H H CF₃CH₂(2,2-Difluoro-cyclopropyl) Cl Me Me H H 1 H H ClCH₂(2,2-Difluoro-cyclopropyl) CF₃ Me Me H H 1 H H CF₃ CH₂Bu-c Cl Me Me HH 1 H H Cl CH₂Bu-c CF₃ Me Me H H 1 H H CF₃ CH₂Pen-c Cl Me Me H H 1 H HCl CH₂Pen-c CF₃ Me Me H H 1 H H CF₃ CH₂Hex-c Cl Me Me H H 1 H H ClCH₂Hex-c CF₃ Me Me H H 1 H H CF₃ CH₂CH₂Pr-c Cl Me Me H H 1 H H ClCH₂CH₂Pr-c CF₃ Me Me H H 1 H H CF₃ CH₂CH═CH₂ Cl Me Me H H 1 H H ClCH₂CH═CH₂ CF₃ Me Me H H 1 H H CF₃ CH₂CH═CH Cl Me Me H H 1 H H ClCH₂CH═CH CF₃ Me Me H H 1 H H Cl CH₂C≡CH Cl Me Me H H 1 H H OCHF₂ CH₂C≡CHCl Me Me H H 1 H H Cl CH₂C≡CH OCHF₂ Me Me H H 1 H H OCHF₂ CH₂C≡CH OCHF₂Me Me H H 1 H H CF₃ CH₂C≡CH F Me Me H H 1 H H F CH₂C≡CH CF₃ Me Me H H 1H H CF₃ CH₂C≡CH Cl Me Me H H 1 H H Cl CH₂C≡CH CF₃ Me Me H H 1 H H CF₃CH₂C≡CH OMe Me Me H H 1 H H OMe CH₂C≡CH CF₃ Me Me H H 1 H H CF₃ CH₂C≡CHOEt Me Me H H 1 H H OEt CH₂C≡CH CF₃ Me Me H H 1 H H CF₃ CH₂C≡CH OCHF₂ MeMe H H 1 H H OCHF₂ CH₂C≡CH CF₃ Me Me H H 1 H H CF₃ CH₂C≡CH CN Me Me H H1 H H CN CH₂C≡CH CF₃ Me Me H H 1 H H CF₃ CH₂C≡CH Me Me Me H H 1 H H MeCH₂C≡CH CF₃ Me Me H H 1 H H CF₃ CHMeC≡CH Cl Me Me H H 1 H H Cl CHMeC≡CHCF₃ Me Me H H 1 H H CF₃ CH₂C≡CMe Cl Me Me H H 1 H H Cl CH₂C≡CMe CF₃ MeMe H H 1 H H Cl CHF₂ Cl Me Me H H 1 H H OCHF₂ CHF₂ Cl Me Me H H 1 H H ClCHF₂ OCHF₂ Me Me H H 1 H H OCHF₂ CHF₂ OCHF₂ Me Me H H 1 H H CF₃ CHF₂ ClMe Me H H 1 H H Cl CHF₂ CF₃ Me Me H H 1 H H CF₃ CHF₂ F Me Me H H 1 H H FCHF₂ CF₃ Me Me H H 1 H H CF₃ CHF₂ OMe Me Me H H 1 H H OMe CHF₂ CF₃ Me MeH H 1 H H CF₃ CHF₂ OEt Me Me H H 1 H H OEt CHF₂ CF₃ Me Me H H 1 H H CF₃CHF₂ OCHF₂ Me Me H H 1 H H OCHF₂ CHF₂ CF₃ Me Me H H 1 H H CF₃ CHF₂ CN MeMe H H 1 H H CN CHF₂ CF₃ Me Me H H 1 H H CF₃ CHF₂ Me Me Me H H 1 H H MeCHF₂ CF₃ Me Me H H 1 H H Me CHF₂ Cl Me Me H H 1 H H Cl CHF₂ Me Me Me H H1 H H Et CHF₂ Cl Me Me H H 1 H H Cl CHF₂ Et Me Me H H 1 H H CF₃ CH₂CHF₂Cl Me Me H H 1 H H Cl CH₂CHF₂ CF₃ Me Me H H 1 H H CF₃ CH₂CF₃ Cl Me Me HH 1 H H Cl CH₂CF₃ CF₃ Me Me H H 1 H H CF₃ CH₂OH Cl Me Me H H 1 H H ClCH₂OH CF₃ Me Me H H 1 H H Cl CH₂OMe Cl Me Me H H 1 H H OCHF₂ CH₂OMe ClMe Me H H 1 H H Cl CH₂OMe OCHF₂ Me Me H H 1 H H OCHF₂ CH₂OMe OCHF₂ Me MeH H 1 H H CF₃ CH₂OMe F Me Me H H 1 H H F CH₂OMe CF₃ Me Me H H 1 H H CF₃CH₂OMe Cl Me Me H H 1 H H Cl CH₂OMe CF₃ Me Me H H 1 H H CF₃ CH₂OMe OMeMe Me H H 1 H H OMe CH₂OMe CF₃ Me Me H H 1 H H CF₃ CH₂OMe OEt Me Me H H1 H H OEt CH₂OMe CF₃ Me Me H H 1 H H CF₃ CH₂OMe OCHF₂ Me Me H H 1 H HOCHF₂ CH₂OMe CF₃ Me Me H H 1 H H CF₃ CH₂OMe CN Me Me H H 1 H H CN CH₂OMeCF₃ Me Me H H 1 H H CF₃ CH₂OMe Me Me Me H H 1 H H Me CH₂OMe CF₃ Me Me HH 1 H H CF₃ CH₂OEt Cl Me Me H H 1 H H Cl CH₂OEt CF₃ Me Me H H 1 H H CF₃CH₂CH₂OH Cl Me Me H H 1 H H Cl CH₂CH₂OH CF₃ Me Me H H 1 H H CF₃CH₂CH₂OMe Cl Me Me H H 1 H H Cl CH₂CH₂OMe CF₃ Me Me H H 1 H H CF₃CH₂CH₂OEt Cl Me Me H H 1 H H Cl CH₂CH₂OEt CF₃ Me Me H H 1 H H CF₃CH₂NHMe Cl Me Me H H 1 H H Cl CH₂NHMe CF₃ Me Me H H 1 H H CF₃ CH₂N(Me)₂Cl Me Me H H 1 H H Cl CH₂N(Me)₂ CF₃ Me Me H H 1 H H CF₃ CH₂N(Me)C(═O)MeCl Me Me H H 1 H H Cl CH₂N(Me)C(═O)Me CF₃ Me Me H H 1 H H CF₃CH₂N(Me)C(═O)CF₃ Cl Me Me H H 1 H H Cl CH₂N(Me)C(═O)CF₃ CF₃ Me Me H H 1H H CF₃ CH₂N(Me)SO₂Me Cl Me Me H H 1 H H Cl CH₂N(Me)SO₂Me CF₃ Me Me H H1 H H CF₃ CH₂N(Me)SO₂CHF₂ Cl Me Me H H 1 H H Cl CH₂N(Me)SO₂CHF₂ CF₃ MeMe H H 1 H H CF₃ CH₂N(Me)SO₂CF₃ Cl Me Me H H 1 H H Cl CH₂N(Me)SO₂CF₃ CF₃Me Me H H 1 H H CF₃ CH₂SMe Cl Me Me H H 1 H H Cl CH₂SMe CF₃ Me Me H H 1H H CF₃ CH₂SO₂Me Cl Me Me H H 1 H H Cl CH₂SO₂Me CF₃ Me Me H H 1 H H CF₃CH₂CH₂SMe Cl Me Me H H 1 H H Cl CH₂CH₂SMe CF₃ Me Me H H 1 H H CF₃CH₂CH₂SO₂Me Cl Me Me H H 1 H H Cl CH₂CH₂SO₂Me CF₃ Me Me H H 1 H H CF₃CH₂CN Cl Me Me H H 1 H H Cl CH₂CN CF₃ Me Me H H 1 H H CF₃ CH₂C(═O)OMe ClMe Me H H 1 H H Cl CH₂C(═O)OMe CF₃ Me Me H H 1 H H CF₃ CH₂C(═O)OEt Cl MeMe H H 1 H H Cl CH₂C(═O)OEt CF₃ Me Me H H 1 H H CF₃ CH(Me)C(═O)OMe Cl MeMe H H 1 H H Cl CH(Me)C(═)OMe CF₃ Me Me H H 1 H H CF₃ C(Me)₂C(═O)OMe ClMe Me H H 1 H H Cl C(Me)₂C(═O)OMe CF₃ Me Me H H 1 H H CF₃ CH₂C(═)NH₂ ClMe Me H H 1 H H Cl CH₂C(═O)NH₂ CF₃ Me Me H H 1 H H CF₃ CH₂C(═O)NHMe ClMe Me H H 1 H H Cl CH₂C(═O)NHMe CF₃ Me Me H H 1 H H CF₃ CH₂C(═O)N(Me)₂Cl Me Me H H 1 H H Cl CH₂C(═O)N(Me)₂ CF₃ Me Me H H 1 H H CF₃ CH₂C(═O)MeCl Me Me H H 1 H H Cl CH₂C(═O)Me CF₃ Me Me H H 1 H H CF₃ CH₂C(NOMe)Me ClMe Me H H 1 H H Cl CH₂C(NOMe)Me CF₃ Me Me H H 1 H H CF₃ CH₂C(═O)CF₃ ClMe Me H H 1 H H Cl CH₂C(═O)CF₃ CF₃ Me Me H H 1 H H CF₃ CH₂CH₂C(═O)Me ClMe Me H H 1 H H Cl CH₂CH₂C(═O)Me CF₃ Me Me H H 1 H H Me Ph Me Me Me H H1 H H Me Ph Cl Me Me H H 1 H H Et Ph Cl Me Me H H 1 H H Pr Ph Cl Me Me HH 1 H H Pr-i Ph Cl Me Me H H 1 H H Bu-t Ph Cl Me Me H H 1 H H CH₂OMe PhCl Me Me H H 1 H H Cl Ph Cl Me Me H H 1 H H OCHF₂ Ph Cl Me Me H H 1 H HOCHF₂ Ph OCHF₂ Me Me H H 1 H H CHF₂ Ph Cl Me Me H H 1 H H CF₃ Ph H Me MeH H 1 H H CF₃ Ph Me Me Me H H 1 H H Me Ph CF₃ Me Me H H 1 H H CF₃ Ph EtMe Me H H 1 H H CF₃ Ph Pr-i Me Me H H 1 H H CF₃ Ph CHF₂ Me Me H H 1 H HCF₃ Ph CF₃ Me Me H H 1 H H CF₃ Ph F Me Me H H 1 H H CF₃ Ph Cl Me Me H H1 H H Cl Ph CF₃ Me Me H H 1 H H CF₃ Ph OH Me Me H H 1 H H OH Ph CF₃ MeMe H H 1 H H CF₃ Ph OMe Me Me H H 1 H H OMe Ph CF₃ Me Me H H 1 H H CF₃Ph OEt Me Me H H 1 H H OEt Ph CF₃ Me Me H H 1 H H CF₃ Ph OPr-i Me Me H H1 H H CF₃ Ph OPr Me Me H H 1 H H CF₃ Ph OBu-t Me Me H H 1 H H CF₃ PhOCH₂Pr-c Me Me H H 1 H H CF₃ Ph OCH₂CH═CH₂ Me Me H H 1 H H CF₃ PhOCH₂C≡CH Me Me H H 1 H H CF₃ Ph OCHF₂ Me Me H H 1 H H OCHF₂ Ph CF₃ Me MeH H 1 H H CF₃ Ph OCH₂CHF₂ Me Me H H 1 H H CF₃ Ph OCH₂CF₃ Me Me H H 1 H HCF₃ Ph OCH₂C(═O)OMe Me Me H H 1 H H CF₃ Ph OCH(Me)C(═O)OMe Me Me H H 1 HH CF₃ Ph OC(Me)₂C(═O)OMe Me Me H H 1 H H CF₃ Ph OC(═O)Me Me Me H H 1 H HCF₃ Ph OC(═O)Et Me Me H H 1 H H CF₃ Ph OC(═O)CH₂Ph Me Me H H 1 H H CF₃Ph OC(═O)CF₃ Me Me H H 1 H H CF₃ Ph OC(═O)Ph Me Me H H 1 H H CF₃ PhOSO₂Me Me Me H H 1 H H CF₃ Ph OSO₂Et Me Me H H 1 H H CF₃ Ph OSO₂CH₂Ph MeMe H H 1 H H CF₃ Ph OSO₂CF₃ Me Me H H 1 H H CF₃ Ph OSO₂Ph Me Me H H 1 HH CF₃ Ph SMe Me Me H H 1 H H CF₃ Ph SO₂Me Me Me H H 1 H H CF₃ Ph SEt MeMe H H 1 H H CF₃ Ph SO₂Et Me Me H H 1 H H CF₃ Ph SPr-i Me Me H H 1 H HCF₃ Ph SO₂Pr-i Me Me H H 1 H H CF₃ Ph SPr Me Me H H 1 H H CF₃ Ph SO₂PrMe Me H H 1 H H CF₃ Ph SBu-t Me Me H H 1 H H CF₃ Ph SO₂Bu-t Me Me H H 1H H CF₃ Ph SCHF₂ Me Me H H 1 H H CF₃ Ph SO₂CHF₂ Me Me H H 1 H H CF₃ PhNH₂ Me Me H H 1 H H CF₃ Ph NHMe Me Me H H 1 H H CF₃ Ph N(Me)₂ Me Me H H1 H H CF₃ Ph NHC(═O)Me Me Me H H 1 H H CF₃ Ph N(Me)C(═O)Me Me Me H H 1 HH CF₃ Ph NHSO₂Me Me Me H H 1 H H CF₃ Ph N(Me)SO₂Me Me Me H H 1 H H CF₃Ph NHSO₂CF₃ Me Me H H 1 H H CF₃ Ph N(Me)SO₂CF₃ Me Me H H 1 H H CF₃ PhNHPh Me Me H H 1 H H CF₃ Ph N(Me)Ph Me Me H H 1 H H CF₃ Ph CN Me Me H H1 H H CF₃ Ph C(═O)Me Me Me H H 1 H H CF₃ Ph C(═O)OMe Me Me H H 1 H H CF₃Ph C(═O)NH₂ Me Me H H 1 H H CF₃ Ph C(═O)NHMe Me Me H H 1 H H CF₃ PhC(═O)N(Me)₂ Me Me H H 1 H H CF₃ Ph Imidazol-1-yl Me Me H H 1 H H CF₃ PhPyrazol-1-yl Me Me H H 1 H H CF₃ Ph 1,2,4-Triazoi-1-yl Me Me H H 1 H HCF₃ Ph 1,2,4-Triazol-4-yl Me Me H H 1 H H CF₃ Ph Tetrazol-1-yl Me Me H H1 H H CF₃ Ph Tetrazol-5-yl Me Me H H 1 H H CF₃ Ph(4,6-Dimethoxypyrimidin-2-yl)oxy Me Me H H 1 H H CF₃ Ph(4,6-Dimethoxypyrimidin-2-yl) sulfonyl Me Me H H 1 H H CF₂CF₃ Ph Cl MeMe H H 1 H H CF₃ (2-Cl)Ph Cl Me Me H H 1 H H CF₃ (2-F)Ph Cl Me Me H H 1H H CF₃ (2-OMe)Ph Cl Me Me H H 1 H H CF₃ (2-Me)Ph Cl Me Me H H 1 H H CF₃(2-NO₂)Ph Cl Me Me H H 1 H H CF₃ (2-CN)Ph Cl Me Me H H 1 H H CF₃(2-C(═O)Me)Ph Cl Me Me H H 1 H H CF₃ (2-C(═O)OMe)Ph Cl Me Me H H 1 H HCF₃ (2-C(═O)OEt)Ph Cl Me Me H H 1 H H CF₃ (2-C(═O)OPr-i)Ph Cl Me Me H H1 H H CF₃ (2-C(═O)NH₂)Ph Cl Me Me H H 1 H H CF₃ (2-C(═O)NHMe)Ph Cl Me MeH H 1 H H CF₃ (2-C(═O)NMe₂)Ph Cl Me Me H H 1 H H CF₃ (3-Cl)Ph Cl Me Me HH 1 H H CF₃ (3-F)Ph Cl Me Me H H 1 H H CF₃ (3-OMe)Ph Cl Me Me H H 1 H HCF₃ (3-Me)Ph Cl Me Me H H 1 H H CF₃ (3-NO₂)Ph Cl Me Me H H 1 H H CF₃(3-CN)Ph Cl Me Me H H 1 H H CF₃ (3-C(═O)Me)Ph Cl Me Me H H 1 H H CF₃(3-C(═O)OMe)Ph Cl Me Me H H 1 H H CF₃ (3-C(═O)OEt)Ph Cl Me Me H H 1 H HCF₃ (3-C(═O)OPr-i)Ph Cl Me Me H H 1 H H CF₃ (3-C(═O)NH₂)Ph Cl Me Me H H1 H H CF₃ (3-C(═O)NHMe)Ph Cl Me Me H H 1 H H CF₃ (3-C(═O)NMe₂)Ph Cl MeMe H H 1 H H CF₃ (4-Cl)Ph Cl Me Me H H 1 H H CF₃ (4-F)Ph Cl Me Me H H 1H H CF₃ (4-OMe)Ph Cl Me Me H H 1 H H CF₃ (4-Me)Ph Cl Me Me H H 1 H H CF₃(4-NO₂)Ph Cl Me Me H H 1 H H CF₃ (4-CN)Ph Cl Me Me H H 1 H H CF₃(4-C(═O)Me)Ph Cl Me Me H H 1 H H CF₃ (4-C(═O)OMe)Ph Cl Me Me H H 1 H HCF₃ (4-C(═O)OEt)Ph Cl Me Me H H 1 H H CF₃ (4-C(═O)OPr-i)Ph Cl Me Me H H1 H H CF₃ (4-C(═O)NH₂)Ph Cl Me Me H H 1 H H CF₃ (4-C(═O)NHMe)Ph Cl Me MeH H 1 H H CF₃ (4-C(═O)NMe₂)Ph Cl Me Me H H 1 H H CF₃ Pyrmidin-2-yl Cl MeMe H H 1 H H CF₃ 4,6-Dimethoxypyrmidin-2-yl Cl Me Me H H 1 H H CF₃Thiophen-2-yl Cl Me Me H H 1 H H CF₃ Furan-2-yl Cl Me Me H H 1 H H CF₃SO₂Me Cl Me Me H H 1 H H CF₃ SO₂Et Cl Me Me H H 1 H H CF₃ SO₂Pr-i Cl MeMe H H 1 H H CF₃ SO₂CH₂Ph Cl Me Me H H 1 H H CF₃ SO₂CHF₂ Cl Me Me H H 1H H CF₃ SO₂CF₃ Cl Me Me H H 1 H H CF₃ SO₂Ph Cl Me Me H H 1 H H CF₃C(═O)Me Cl Me Me H H 1 H H CF₃ C(═O)Et Cl Me Me H H 1 H H CF₃ C(═O)Pr-iCl Me Me H H 1 H H CF₃ C(═O)Bu-t Cl Me Me H H 1 H H CF₃ C(═O)Ph Cl Me MeH H 1 H H CF₃ C(═O)CH₂Ph Cl Me Me H H 1 H H CF₃ C(═O)CH₂Cl Cl Me Me H H1 H H CF₃ C(═O)CHCl₂ Cl Me Me H H 1 H H CF₃ C(═O)CF₃ Cl Me Me H H 1 H HCF₃ C(═O)OMe Cl Me Me H H 1 H H CF₃ C(═O)OPh Cl Me Me H H 1 H H CF₃C(═O)OCH₂Ph Cl Me Me H H 1 H H CF₃ C(═O)NHMe Cl Me Me H H 1 H H CF₃C(═O)N(Me)₂ Cl Me Me H H 1 H H CF₃ C(═O)NHPh Cl Me Me H H 1 H H CF₃ NH₂Cl Me Me H H 1 H H Cl —(CH₂)₂O— Me Me H H 1 H H Cl —(CH₂)₃O— Me Me H H 1H H Cl —(CH₂)₃S— Me Me H H 1 H H Cl —(CH₂)₃SO₂— Me Me H H 1 H H CF₃—(CH₂)₂O— Me Me H H 1 H H CF₃ —(CH₂)₃O— Me Me H H 1 H H CF₃ —(CH₂)₃S— MeMe H H 1 H H CF₃ —(CH₂)₃SO₂— Me Me H H 1 H H OMe —(CH₂)₄— Me Me H H 1 HH OCHF₂ —(CH₂)₄— H H H H 1 H H CF₃ Me Cl Me H H H 1 H H CF₃ Me Cl Me HMe H 1 H H CF₃ Me Cl Me Me Me H 1 H H CF₃ Me Cl Me Me H H 1 Me H CF₃ MeCl Me Me H H 1 Et H CF₃ Me Cl Me Me H H 1 Pr-i H CF₃ Me Cl Me Me H H 1Me Me CF₃ Me Cl Me Et H H 1 H H CF₃ Me Cl Et Et H H 1 H H CF₃ Me Cl MePr-i H H 1 H H CF₃ Me Cl Me Pr H H 1 H H CF₃ Me Cl Me Pr-c H H 1 H H CF₃Me Cl Me CH₂Pr-c H H 1 H H CF₃ Me Cl —(CH₂)₂— H H 1 H H CF₃ Me Cl—(CH₂)₃— H H 1 H H CF₃ Me Cl —(CH₂)₄— H H 1 H H CF₃ Me Cl —(CH₂)₅— H H 1H H CF₃ Me Cl H —(CH₂)₃— H 1 H H CF₃ Me Cl H —(CH₂)₄— H 1 H H CF₃ Me ClH —(CH₂)₅— H 1 H H CF₃ Me Cl H —(CH₂)₆— H 1 H H CF₃ Me Cl Me Me H H 0 HH Cl H Cl Me Me H H 0 H H OCHF₂ H Cl Me Me H H 0 H H OCHF₂ H OCHF₂ Me MeH H 0 H H CHF₂ H Cl Me Me H H 0 H H CF₃ H F Me Me H H 0 H H CF₃ H Cl MeMe H H 0 H H CF₃ H OMe Me Me H H 0 H H CF₃ H OEt Me Me H H 0 H H CF₃ HOCHF₂ Me Me H H 0 H H CF₃ H CN Me Me H H 0 H H CF₃ H Me Me Me H H 0 H HH Me Cl Me Me H H 0 H H Me Me Me Me Me H H 0 H H Me Me Cl Me Me H H 0 HH CL Me Me Me Me H H 0 H H Et Me Cl Me Me H H 0 H H Cl Me Et Me Me H H 0H H Pr-i Me Cl Me Me H H 0 H H Cl Me Pr-i Me Me H H 0 H H Bu-t Me Cl MeMe H H 0 H H Cl Me Bu-t Me Me H H 0 H H Cl Me Cl Me Me H H 0 H H CHF₂ MeCl Me Me H H 0 H H Cl Me CHF₂ Me Me H H 0 H H OCHF₂ Me H Me Me H H 0 H HOCHF₂ Me Cl Me Me H H 0 H H Cl Me OCHF₂ Me Me H H 0 H H OCHF₂ Me OCHF₂Me Me H H 0 H H CF₃ Me H Me Me H H 0 H H CF₃ Me Cl Me Me H H 0 H H Cl MeCF₃ Me Me H H 0 H H CF₃ Me F Me Me H H 0 H H F Me CF₃ Me Me H H 0 H HCF₃ Me OH Me Me H H 0 H H OH Me CF₃ Me Me H H 0 H H CF₃ Me OMe Me Me H H0 H H OMe Me CF₃ Me Me H H 0 H H CF₃ Me OEt Me Me H H 0 H H OEt Me CF₃Me Me H H 0 H H CF₃ Me OPr-i Me Me H H 0 H H CF₃ Me OPr Me Me H H 0 H HCF₃ Me OBu-t Me Me H H 0 H H CF₃ Me OBu-s Me Me H H 0 H H CF₃ Me OBu-iMe Me H H 0 H H CF₃ Me OBu Me Me H H 0 H H CF₃ Me O(2-Pen) Me Me H H 0 HH CF₃ Me O(3-Pen) Me Me H H 0 H H CF₃ Me OPen-n Me Me H H 0 H H CF₃ MeO(2-Hex) Me Me H H 0 H H CF₃ Me O(3-Hex) Me Me H H 0 H H CF₃ Me OHex-nMe Me H H 0 H H CF₃ Me OPen-c Me Me H H 0 H H CF₃ Me OHex-c Me Me H H 0H H CF₃ Me OCH₂Pr-c Me Me H H 0 H H CF₃ Me OCH₂Bu-c Me Me H H 0 H H CF₃Me OCH₂Pen-c Me Me H H 0 H H CF₃ Me OCH₂Hex-c Me Me H H 0 H H CF₃ MeOCH₂CH═CH₂ Me Me H H 0 H H CF₃ Me OCH₂C*CH Me Me H H 0 H H CF₃ Me OCHF₂Me Me H H 0 H H OCHF₂ Me CF₃ Me Me H H 0 H H CF₃ Me OCH₂CHF₂ Me Me H H 0H H OCH₂CHF₂ Me CF₃ Me Me H H 0 H H CF₃ Me OCH₂CF₃ Me Me H H 0 H HOCH₂CF₃ Me CF₃ Me Me H H 0 H H CF₃ Me OCH₂CN Me Me H H 0 H H CF₃ MeOCH₂C(═)OEt Me Me H H 0 H H CF₃ Me OCH(Me)C(═O)OEt Me Me H H 0 H H CF₃Me OCH₂C(═O)NH₂ Me Me H H 0 H H CF₃ Me OCH₂C(═O)NHMe Me Me H H 0 H H CF₃Me OCH₂C(═O)N(Me)₂ Me Me H H 0 H H CF₃ Me OCH₂Ph Me Me H H 0 H H CF₃ MeOPh Me Me H H 0 H H CF₃ Me O(2-CL)Ph Me Me H H 0 H H CF₃ Me O(2-Br)Ph MeMe H H 0 H H CF₃ Me O(2-F)Ph Me Me H H 0 H H CF₃ Me O(2-Me)Ph Me Me H H0 H H CF₃ Me O(2-OMe)Ph Me Me H H 0 H H CF₃ Me O(2-NO₂)Ph Me Me H H 0 HH CF₃ Me Q(2-CN)Ph Me Me H H 0 H H CF₃ Me O(2-C(═O)OMe)Ph Me Me H H 0 HH CF₃ Me O(3-Cl)Ph Me Me H H 0 H H CF₃ Me O(3-Br)Ph Me Me H H 0 H H CF₃Me O(3-F)Ph Me Me H H 0 H H CF₃ Me O(3-Me)Ph Me Me H H 0 H H CF₃ MeO(3-OMe)Ph Me Me H H 0 H H CF₃ Me O(3-NO₂)Ph Me Me H H 0 H H CF₃ MeO(3-CN)Ph Me Me H H 0 H H CF₃ Me O(3-C(═O)OMe)Ph Me Me H H 0 H H CF₃ MeO(4-Cl)Ph Me Me H H 0 H H CF₃ Me O(4-Br)Ph Me Me H H 0 H H CF₃ MeO(4-F)Ph Me Me H H 0 H H CF₃ Me O(4-Me)Ph Me Me H H 0 H H CF₃ MeO(4-OMe)Ph Me Me H H 0 H H CF₃ Me O(4-NO₂)Ph Me Me H H 0 H H CF₃ MeO(4-CN)Ph Me Me H H 0 H H CF₃ Me O(4-C(═O)OMe)Ph Me Me H H 0 H H CF₃ MeOC(═O)Me Me Me H H 0 H H CF₃ Me OC(═O)Et Me Me H H 0 H H CF₃ MeOC(═O)CH₂Ph Me Me H H 0 H H CF₃ Me OC(═O)CF₃ Me Me H H 0 H H CF₃ MeOC(═O)Ph Me Me H H 0 H H CF₃ Me OSO₂Me Me Me H H 0 H H CF₃ Me OSO₂Et MeMe H H 0 H H CF₃ Me OSO₂CH₂Ph Me Me H H 0 H H CF₃ Me OSO₂CF₃ Me Me H H 0H H CF₃ Me OSO₂Ph Me Me H H 0 H H CF₃ Me SMe Me Me H H 0 H H CF₃ MeSO₂Me Me Me H H 0 H H CF₃ Me SEt Me Me H H 0 H H CF₃ Me SO₂Et Me Me H H0 H H CF₃ Me SPr Me Me H H 0 H H CF₃ Me SO₂Pr Me Me H H 0 H H CF₃ MeSPr-i Me Me H H 0 H H CF₃ Me SO₂Pr-i Me Me H H 0 H H CF₃ Me SBu-t Me MeH H 0 H H CF₃ Me SO₂Bu-t Me Me H H 0 H H CF₃ Me SCHF₂ Me Me H H 0 H HCF₃ Me SO₂CHF₂ Me Me H H 0 H H CF₃ Me SCF₃ Me Me H H 0 H H CF₃ Me SO₂CF₃Me Me H H 0 H H CF₃ Me SPh Me Me H H 0 H H CF₃ Me SO₂Ph Me Me H H 0 H HCF₃ Me SCH₂Ph Me Me H H 0 H H CF₃ Me SO₂CH₂Ph Me Me H H 0 H H CF₃ MeSCH₂C(═O)OEt Me Me H H 0 H H CF₃ Me SO₂CH₂C(═O)OEt Me Me H H 0 H H CF₃Me SCH(Me)C(═O)OEt Me Me H H 0 H H CF₃ Me SO₂CH(Me)C(═O)OEt Me Me H H 0H H CF₃ Me SCH₂C(═O)NH₂ Me Me H H 0 H H CF₃ Me SO₂CH₂C(═O)NH₂ Me Me H H0 H H CF₃ Me SCH₂C(═O)NHMe Me Me H H 0 H H CF₃ Me SO₂CH₂C(═O)NHMe Me MeH H 0 H H CF₃ Me SCH₂C(═O)N(Me)₂ Me Me H H 0 H H CF₃ MeSO₂CH₂C(═O)N(Me)₂ Me Me H H 0 H H CF₃ Me NH₂ Me Me H H 0 H H CF₃ Me NHMeMe Me H H 0 H H CF₃ Me N(Me)₂ Me Me H H 0 H H CF₃ Me NHC(═O)Me Me Me H H0 H H CF₃ Me N(Me)C(═O)Me Me Me H H 0 H H CF₃ Me NHSO₂Me Me Me H H 0 H HCF₃ Me N(Me)SO₂Me Me Me H H 0 H H CF₃ Me NHSO₂CHF₂ Me Me H H 0 H H CF₃Me N(Me)SO₂CHF₂ Me Me H H 0 H H CF₃ Me NHSO₂CF₃ Me Me H H 0 H H CF₃ MeN(Me)SO₂CF₃ Me Me H H 0 H H CF₃ Me NHPh Me Me H H 0 H H CF₃ Me N(Me)PhMe Me H H 0 H H CF₃ Me CN Me Me H H 0 H H CN Me CF₃ Me Me H H 0 H H CF₃Me C(═O)OMe Me Me H H 0 H H CF₃ Me C(═O)OCH₂Ph Me Me H H 0 H H CF₃ MeC(═O)OPh Me Me H H 0 H H CF₃ Me C(═O)NH₂ Me Me H H 0 H H CF₃ MeC(═O)NHMe Me Me H H 0 H H CF₃ Me C(═O)N(Me)₂ Me Me H H 0 H H CF₃ MeC(═O)Me Me Me H H 0 H H CF₃ Me C(═O)CF₃ Me Me H H 0 H H CF₃ MeC(═O)CH₂Ph Me Me H H 0 H H CF₃ Me C(═O)Ph Me Me H H 0 H H CF₃ Me Me MeMe H H 0 H H Me Me CF₃ Me Me H H 0 H H CF₃ Me Et Me Me H H 0 H H CF₃ MePr-i Me Me H H 0 H H CF₃ Me Pr Me Me H H 0 H H CF₃ Me CH₂OMe Me Me H H 0H H CF₃ Me CF₃ Me Me H H 0 H H CF₃ Me CHF₂ Me Me H H 0 H H CF₃ Me Ph MeMe H H 0 H H CF₂CF₃ Me Cl Me Me H H 0 H H Ph Me Me Me Me H H 0 H H Ph MeCl Me Me H H 0 H H Ph Me OEt Me Me H H 0 H H Ph Me CF₃ Me Me H H 0 H HPh Me Ph Me Me H H 0 H H Cl Et Cl Me Me H H 0 H H OCHF₂ Et Cl Me Me H H0 H H Cl Et OCHF₂ Me Me H H 0 H H OCHF₂ Et OCHF₂ Me Me H H 0 H H CF₃ EtF Me Me H H 0 H H F Et CF₃ Me Me H H 0 H H CF₃ Et Cl Me Me H H 0 H H ClEt CF₃ Me Me H H 0 H H CF₃ Et OMe Me Me H H 0 H H OMe Et CF₃ Me Me H H 0H H CF₃ Et OEt Me Me H H 0 H H OEt Et CF₃ Me Me H H 0 H H CF₃ Et OCHF₂Me Me H H 0 H H OCHF₂ Et CF₃ Me Me H H 0 H H CF₃ Et CN Me Me H H 0 H HCN Et CF₃ Me Me H H 0 H H CF₃ Et Me Me Me H H 0 H H Me Et CF₃ Me Me H H0 H H Cl Pr-i Cl Me Me H H 0 H H OCHF₂ Pr-i Cl Me Me H H 0 H H Cl Pr-iOCHF₂ Me Me H H 0 H H OCHF₂ Pr-i OCHF₂ Me Me H H 0 H H CF₃ Pr-i F Me MeH H 0 H H F Pr-i CF₃ Me Me H H 0 H H CF₃ Pr-i Cl Me Me H H 0 H H Cl Pr-iCF₃ Me Me H H 0 H H CF₃ Pr-i OMe Me Me H H 0 H H OMe Pr-i CF₃ Me Me H H0 H H CF₃ Pr-i OEt Me Me H H 0 H H OEt Pr-i CF₃ Me Me H H 0 H H CF₃ Pr-iOCHF₂ Me Me H H 0 H H OCHF₂ Pr-i CF₃ Me Me H H 0 H H CF₃ Pr-i CN Me Me HH 0 H H CN Pr-i CF₃ Me Me H H 0 H H CF₃ Pr-i Me Me Me H H 0 H H Me Pr-iCF₃ Me Me H H 0 H H Cl Pr Cl Me Me H H 0 H H OCHF₂ Pr Cl Me Me H H 0 H HCl Pr OCHF₂ Me Me H H 0 H H OCHF₂ Pr OCHF₂ Me Me H H 0 H H CF₃ Pr F MeMe H H 0 H H F Pr CF₃ Me Me H H 0 H H CF₃ Pr Cl Me Me H H 0 H H Cl PrCF₃ Me Me H H 0 H H CF₃ Pr OMe Me Me H H 0 H H OMe Pr CF₃ Me Me H H 0 HH CF₃ Pr OEt Me Me H H 0 H H OEt Pr CF₃ Me Me H H 0 H H CF₃ Pr OCHF₂ MeMe H H 0 H H OCHF₂ Pr CF₃ Me Me H H 0 H H CF₃ Pr CN Me Me H H 0 H H CNPr CF₃ Me Me H H 0 H H CF₃ Pr Me Me Me H H 0 H H Me Pr CF₃ Me Me H H 0 HH Cl Bu-t Cl Me Me H H 0 H H OCHF₂ Bu-t Cl Me Me H H 0 H H OCHF₂ Bu-tOCHF₂ Me Me H H 0 H H CF₃ Bu-t H Me Me H H 0 H H CF₃ Bu-t F Me Me H H 0H H CF₃ Bu-t Cl Me Me H H 0 H H Cl Bu-t CF₃ Me Me H H 0 H H CF₃ Bu-t OMeMe Me H H 0 H H OMe Bu-t CF₃ Me Me H H 0 H H CF₃ Bu-t OEt Me Me H H 0 HH OEt Bu-t CF₃ Me Me H H 0 H H CF₃ Bu-t OCHF₂ Me Me H H 0 H H CF₃ Bu-tCN Me Me H H 0 H H CF₃ Bu-t Me Me Me H H 0 H H Me Bu-t CF₃ Me Me H H 0 HH CF₃ Bu-s Cl Me Me H H 0 H H Cl Bu-s CF₃ Me Me H H 0 H H CF₃ Bu-i Cl MeMe H H 0 H H Cl Bu-i CF₃ Me Me H H 0 H H CF₃ Bu Cl Me Me H H 0 H H Cl BuCF₃ Me Me H H 0 H H CF₃ 1-Methylbutyl Cl Me Me H H 0 H H Cl1-Methylbutyl CF₃ Me Me H H 0 H H CF₃ 1-Ethylpropyl Cl Me Me H H 0 H HCl 1-Ethylpropyl CF₃ Me Me H H 0 H H CF₃ 1-Pentyl Cl Me Me H H 0 H H Cl1-Pentyl CF₃ Me Me H H 0 H H CF₃ 1-Methylpentyl Cl Me Me H H 0 H H Cl1-Methylpentyl CF₃ Me Me H H 0 H H CF₃ 2-Ethylbutyl Cl Me Me H H 0 H HCl 2-Ethylbutyl CF₃ Me Me H H 0 H H CF₃ 3,3-Dimethylbutyl Cl Me Me H H 0H H Cl 3,3-Dimethylbutyl CF₃ Me Me H H 0 H H CF₃ 1-Hexyl Cl Me Me H H 0H H Cl 1-Hexyl CF₃ Me Me H H 0 H H CF₃ 1-Heptyl Cl Me Me H H 0 H H Cl1-Heptyl CF₃ Me Me H H 0 H H CF₃ 1-Octyl Cl Me Me H H 0 H H Cl 1-OctylCF₃ Me Me H H 0 H H CF₃ CH₂Pb Cl Me Me H H 0 H H Cl CH₂Ph CF₃ Me Me H H0 H H CF₃ Pr-c Cl Me Me H H 0 H H CF₃ Pen-c Cl Me Me H H 0 H H Cl Pen-cCF₃ Me Me H H 0 H H CF₃ Hex-c Cl Me Me H H 0 H H Cl Hex-c CF₃ Me Me H H0 H H Cl CH₂Pr-c Cl Me Me H H 0 H H OCHF₂ CH₂Pr-c Cl Me Me H H 0 H H ClCH₂Pr-c OCHF₂ Me Me H H 0 H H OCHF₂ CH₂Pr-c OCHF₂ Me Me H H 0 H H CF₃CH₂Pr-c F Me Me H H 0 H H F CH₂Pr-c CF₃ Me Me H H 0 H H CF₃ CH₂Pr-c ClMe Me H H 0 H H Cl CH₂Pr-c CF₃ Me Me H H 0 H H CF₃ CH₂Pr-c CN Me Me H H0 H H CF₃ CH₂Pr-c OH Me Me H H 0 H H CF₃ CH₂Pr-c OMe Me Me H H 0 H H OMeCH₂Pr-c CF₃ Me Me H H 0 H H CF₃ CH₂Pr-c OEt Me Me H H 0 H H OEt CH₂Pr-cCF₃ Me Me H H 0 H H CF₃ CH₂Pr-c OPr-i Me Me H H 0 H H CF₃ CH₂Pr-c OPr MeMe H H 0 H H CF₃ CH₂Pr-c OBu-t Me Me H H 0 H H CF₃ CH₂Pr-c OCH₂Pr-c MeMe H H 0 H H CF₃ CH₂Pr-c OCH₂Bu-c Me Me H H 0 H H CF₃ CH₂Pr-c OPen-c MeMe H H 0 H H CF₃ CH₂Pr-c OCHF₃ Me Me H H 0 H H OCHF₂ CH₂Pr-c CF₃ Me Me HH 0 H H CF₃ CH₂Pr-c CN Me Me H H 0 H H CN CH₂Pr-o CF₃ Me Me H H 0 H HCF₃ CH₂Pr-c Me Me Me H H 0 H H Me CH₂Pr-c CF₃ Me Me H H 0 H H CF₃1-cyclopropylethyl Cl Me Me H H 0 H H Cl 1-cyclopropylethyl CF₃ Me Me HH 0 H H CF₃ CH₂(2-Methyl-cyclopropyl) Cl Me Me H H 0 H H ClCH₂(2-Methyl-cyclopropyl) CF₃ Me Me H H 0 H H CF₃CH₂(2,2-Dimethyl-cycloproppyl) Cl Me Me H H 0 H H ClCH₂(2,2-Dimethyl-cyclopropyl) CF₃ Me Me H H 0 H H CF₃CH₂(2-Chloro-cyclopropyl) Cl Me Me H H 0 H H ClCH₂(2-Chloro-cyclopropyl) CF₃ Me Me H H 0 H H CF₃CH₂(2,2-Dichloro-cyclopropyl) Cl Me Me H H 0 H H ClCH₂(2,2-Dichloro-cyclopropyl) CF₃ Me Me H H 0 H H CF₃CH₂(2-Fluoro-cyclopropyl) Cl Me Me H H 0 H H ClCH₂(2-Fluoro-cyclopropyl) CF₃ Me Me H H 0 H H CF₃CH₂(2,2-Difluoro-cyclopropyl) Cl Me Me H H 0 H H ClCH₂(2,2-Difluoro-cyclopropyl) CF₃ Me Me H H 0 H H CF₃ CH₂Bu-c Cl Me Me HH 0 H H Cl CH₂Bu-c CF₃ Me Me H H 0 H H CF₃ CH₂Pen-c Cl Me Me H H 0 H HCl CH₂Pen-c CF₃ Me Me H H 0 H H CF₃ CH₂Hex-c Cl Me Me H H 0 H H ClCH₂Hex-c CF₃ Me Me H H 0 H H CF₃ CH₂CH₂Pr-c Cl Me Me H H 0 H H ClCH₂CH₂Pr-c CF₃ Me Me H H 0 H H CF₃ CH₂CH═CH₂ Cl Me Me H H 0 H H ClCH₂CH═CH₂ CF₃ Me Me H H 0 H H CF₃ CH₂CH═CHCl Cl Me Me H H 0 H H ClCH₂CH═CHCl CF₃ Me Me H H 0 H H Cl CH₂C≡CH Cl Me Me H H 0 H H OCHF₂CH₂C≡CH Cl Me Me H H 0 H H Cl CH₂C≡CH OCHF₂ Me Me H H 0 H H OCHF₂CH₂C≡CH OCHF Me Me H H 0 H H CF₃ CH₂C≡CH F Me Me H H 0 H H F CH₂C≡CH CF₃Me Me H H 0 H H CF₃ CH₂C≡CH Cl Me Me H H 0 H H Cl CH₂C≡CH CF₃ Me Me H H0 H H CF₃ CH₂C≡CH OMe Me Me H H 0 H H OMe CH₂C≡CH CF₃ Me Me H H 0 H HCF₃ CH₂C≡CH OEt Me Me H H 0 H H OEt CH₂C≡CH CF₃ Me Me H H 0 H H CF₃CH₂C≡CH OCHF₂ Me Me H H 0 H H OCHF₂ CH₂C≡CH CF₃ Me Me H H 0 H H CF₃CH₂C≡CH CN Me Me H H 0 H H CN CH₂C≡CH CF₃ Me Me H H 0 H H CF₃ CH₂C≡CH MeMe Me H H 0 H H Me CH₂C≡CH CF₃ Me Me H H 0 H H CF₃ CH₂C≡CH Cl Me Me H H0 H H Cl CH₂C≡CH CF₃ Me Me H H 0 H H CF₃ CH₂C≡Me Cl Me Me H H 0 H H ClCH₂C≡Me CF₃ Me Me H H 0 H H Cl CHF₂ Cl Me Me H H 0 H H OCHF₂ CHF₂ Cl MeMe H H 0 H H Cl CHF₂ OCHF₂ Me Me H H 0 H H OCHF₂ CHF₂ OCHF₂ Me Me H H 0H H CF₃ CHF₂ Cl Me Me H H 0 H H Cl CHF₂ CF₃ Me Me H H 0 H H CF₃ CHF₂ FMe Me H H 0 H H F CHF₂ CF₃ Me Me H H 0 H H CF₃ CHF₂ OMe Me Me H H 0 H HOMe CHF₂ CF₃ Me Me H H 0 H H CF₃ CHF₂ OEt Me Me H H 0 H H OEt CHF₂ CF₃Me Me H H 0 H H CF₃ CHF₂ OCHF₂ Me Me H H 0 H H OCHF₂ CHF₂ CF₃ Me Me H H0 H H CF₃ CHF₂ CN Me Me H H 0 H H CN CHF₂ CF₃ Me Me H H 0 H H CF₃ CHF₂Me Me Me H H 0 H H Me CHF₂ CF₃ Me Me H H 0 H H Me CHF₂ Cl Me Me H H 0 HH Cl CHF₂ Me Me Me H H 0 H H Et CHF₂ Cl Me Me H H 0 H H Cl CHF₂ Et Me MeH H 0 H H CF₃ CH₂CHF₂ Cl Me Me H H 0 H H Cl CH₂CHF₂ CF₃ Me Me H H 0 H HCF₃ CH₂CF₃ Cl Me Me H H 0 H H Cl CH₂CF₃ CF₃ Me Me H H 0 H H CF₃ CH₂OH ClMe Me H H 0 H H Cl CH₂OH CF₃ Me Me H H 0 H H Cl CH₂OMe Cl Me Me H H 0 HH OCHF₂ CH₂OMe Cl Me Me H H 0 H H Cl CH₂OMe OCHF₂ Me Me H H 0 H H OCHF₂CH₂OMe OCHF₂ Me Me H H 0 H H CF₃ CH₂OMe F Me Me H H 0 H H F CH₂OMe CF₃Me Me H H 0 H H CF₃ CH₂OMe Cl Me Me H H 0 H H Cl CH₂OMe CF₃ Me Me H H 0H H CF₃ CH₂OMe OMe Me Me H H 0 H H OMe CH₂OMe CF₃ Me Me H H 0 H H CF₃CH₂OMe OEt Me Me H H 0 H H OEt CH₂OMe CF₃ Me Me H H 0 H H CF₃ CH₂OMeOCHF₂ Me Me H H 0 H H OCHF₂ CH₂OMe CF₃ Me Me H H 0 H H CF₃ CH₂OMe CN MeMe H H 0 H H CN CH₂OMe CF₃ Me Me H H 0 H H CF₃ CH₂OMe Me Me Me H H 0 H HMe CH₂OMe CF₃ Me Me H H 0 H H CF₃ CH₂OEt Cl Me Me H H 0 H H Cl CH₂OEtCF₃ Me Me H H 0 H H CF₃ CH₂CH₂OH Cl Me Me H H 0 H H Cl CH₂CH₂OH CF₃ MeMe H H 0 H H CF₃ CH₂CH₂OMe Cl Me Me H H 0 H H Cl CH₂CH₂OMe CF₃ Me Me H H0 H H CF₃ CH₂CH₂OEt Cl Me Me H H 0 H H Cl CH₂CH₂OEt CF₃ Me Me H H 0 H HCF₃ CH₂NHMe Cl Me Me H H 0 H H Cl CH₂NHMe CF₃ Me Me H H 0 H H CF₃CH₂N(Me)₂ Cl Me Me H H 0 H H Cl CH₂N(Me)₂ CF₃ Me Me H H 0 H H CF₃CH₂N(Me)C(═O)Me Cl Me Me H H 0 H H Cl CH₂N(Me)C(═O)Me CF₃ Me Me H H 0 HH CF₃ CH₂N(Me)C(═O)CF₃ Cl Me Me H H 0 H H Cl CH₂N(Me)C(═O)CF₃ CF₃ Me MeH H 0 H H CF₃ CH₂N(Me)SO₂Me Cl Me Me H H 0 H H Cl CH₂N(Me)SO₂Me CF₃ MeMe H H 0 H H CF₃ CH₂N(Me)SO₂CHF₂ Cl Me Me H H 0 H H Cl CH₂N(Me)SO₂CHF₂CF₃ Me Me H H 0 H H CF₃ CH₂N(Me)SO₂CF₃ Cl Me Me H H 0 H H ClCH₂N(Me)SO₂CF₃ CF₃ Me Me H H 0 H H CF₃ CH₂SMe Cl Me Me H H 0 H H ClCH₂SMe CF₃ Me Me H H 0 H H CF₃ CH₂SO₂Me Cl Me Me H H 0 H H Cl CH₂SO₂MeCF₃ Me Me H H 0 H H CF₃ CH₂CH₂SMe Cl Me Me H H 0 H H Cl CH₂CH₂SMe CF₃ MeMe H H 0 H H CF₃ CH₂CH₂SO₂Me Cl Me Me H H 0 H H Cl CH₂CH₂SO₂Me CF₃ Me MeH H 0 H H CF₃ CH₂CN Cl Me Me H H 0 H H Cl CH₂CN CF₃ Me Me H H 0 H H CF₃CH₂C(═O)OMe Cl Me Me H H 0 H H Cl CH₂C(═O)OMe CF₃ Me Me H H 0 H H CF₃CH₂C(═O)OEt Cl Me Me H H 0 H H Cl CH₂C(═O)OEt CF₃ Me Me H H 0 H H CF₃CH(Me)C(═O)OMe Cl Me Me H H 0 H H Cl CH(Me)C(═O)OMe CF₃ Me Me H H 0 H HCF₃ C(Me)₂C(═O)OMe Cl Me Me H H 0 H H Cl C(Me)₂C(═O)OMe CF₃ Me Me H H 0H H CF₃ CH₂C(═O)NH₂ Cl Me Me H H 0 H H Cl CH₂C(═O)NH₂ CF₃ Me Me H H 0 HH CF₃ CH₂C(═O)NHMe Cl Me Me H H 0 H H Cl CH₂C(═O)NHMe CF₃ Me Me H H 0 HH CF₃ CH₂C(═O)N(Me)₂ Cl Me Me H H 0 H H Cl CH₂C(═O)N(Me)₂ CF₃ Me Me H H0 H H CF₃ CH₂C(═O)Me Cl Me Me H H 0 H H Cl CH₂C(═O)Me CF₃ Me Me H H 0 HH CF₃ CH₂C(═NOMe)Me Cl Me Me H H 0 H H Cl CH₂C(═NOMe)Me CF₃ Me Me H H 0H H CF₃ CH₂C(═O)CF₃ Cl Me Me H H 0 H H Cl CH₂C(═O)CF₃ CF₃ Me Me H H 0 HH CF₃ CH₂CH₂C(═O)Me Cl Me Me H H 0 H H Cl CH₂CH₂C(═O)Me CF₃ Me Me H H 0H H Me Ph Me Me Me H H 0 H H Me Ph Cl Me Me H H 0 H H Et Ph Cl Me Me H H0 H H Pr Ph Cl Me Me H H 0 H H Pr-i Ph Cl Me Me H H 0 H H Bu-t Ph Cl MeMe H H 0 H H CH₂OMe Ph Cl Me Me H H 0 H H Cl Ph Cl Me Me H H 0 H H OCHF₂Ph Cl Me Me H H 0 H H OCHF₂ Ph OCHF₂ Me Me H H 0 H H CHF₂ Ph Cl Me Me HH 0 H H CF₃ Ph H Me Me H H 0 H H CF₃ Ph Me Me Me H H 0 H H Me Ph CF₃ MeMe H H 0 H H CF₃ Ph Et Me Me H H 0 H H CF₃ Ph Pr-i Me Me H H 0 H H CF₃Ph CHF₂ Me Me H H 0 H H CF₃ Ph CF₃ Me Me H H 0 H H CF₃ Ph F Me Me H H 0H H CF₃ Ph Cl Me Me H H 0 H H Cl Ph CF₃ Me Me H H 0 H H CF₃ Ph OH Me MeH H 0 H H OH Ph CF₃ Me Me H H 0 H H CF₃ Ph OMe Me Me H H 0 H H OMe PhCF₃ Me Me H H 0 H H CF₃ Ph OEt Me Me H H 0 H H OEt Ph CF₃ Me Me H H 0 HH CF₃ Ph OPr-i Me Me H H 0 H H CF₃ Ph OPr Me Me H H 0 H H CF₃ Ph OBu-tMe Me H H 0 H H CF₃ Ph OCH₂Pr-c Me Me H H 0 H H CF₃ Ph OCH₂CH═CH₂ Me MeH H 0 H H CF₃ Ph OCH₂C≡CH Me Me H H 0 H H CF₃ Ph OCHF₂ Me Me H H 0 H HOCHF₂ Ph CF₃ Me Me H H 0 H H CF₃ Ph OCH₂CHF₂ Me Me H H 0 H H CF₃ PhOCH₂CF₃ Me Me H H 0 H H CF₃ Ph OCH₂C(═O)OMe Me Me H H 0 H H CF₃ PhOCH(Me)C(═O)OMe Me Me H H 0 H H CF₃ Ph OC(Me)₂C(═O)OMe Me Me H H 0 H HCF₃ Ph OC(═O)Me Me Me H H 0 H H CF₃ Ph OC(═O)Et Me Me H H 0 H H CF₃ PhOC(═O)CH₂Ph Me Me H H 0 H H CF₃ Ph OC(═O)CF₃ Me Me H H 0 H H CF₃ PhOC(═O)Ph Me Me H H 0 H H CF₃ Ph OSO₂Me Me Me H H 0 H H CF₃ Ph OSO₂Et MeMe H H 0 H H CF₃ Ph OSO₂CH₂Ph Me Me H H 0 H H CF₃ Ph OSO₂CF₃ Me Me H H 0H H CF₃ Ph OSO₂Ph Me Me H H 0 H H CF₃ Ph SMe Me Me H H 0 H H CF₃ PhSO₂Me Me Me H H 0 H H CF₃ Ph SEt Me Me H H 0 H H CF₃ Ph SO₂Et Me Me H H0 H H CF₃ Ph SPr-i Me Me H H 0 H H CF₃ Ph SO₂Pr-i Me Me H H 0 H H CF₃ PhSPr Me Me H H 0 H H CF₃ Ph SO₂Pr Me Me H H 0 H H CF₃ Ph SBu-t Me Me H H0 H H CF₃ Ph SO₂Bu-t Me Me H H 0 H H CF₃ Ph SCHF₂ Me Me H H 0 H H CF₃ PhSO₂CHF₂ Me Me H H 0 H H CF₃ Ph NH₂ Me Me H H 0 H H CF₃ Ph NHMe Me Me H H0 H H CF₃ Ph N(Me)₂ Me Me H H 0 H H CF₃ Ph NHC(═O)Me Me Me H H 0 H H CF₃Ph N(Me)C(═O)Me Me Me H H 0 H H CF₃ Ph NHSO₂Me Me Me H H 0 H H CF₃ PhN(Me)SO₂Me Me Me H H 0 H H CF₃ Ph NHSO₂CF₃ Me Me H H 0 H H CF₃ PhN(Me)SO₂CF₃ Me Me H H 0 H H CF₃ Ph NHPh Me Me H H 0 H H CF₃ Ph N(Me)PhMe Me H H 0 H H CF₃ Ph CN Me Me H H 0 H H CF₃ Ph C(═O)Me Me Me H H 0 H HCF₃ Ph C(═O)OMe Me Me H H 0 H H CF₃ Ph C(═O)NH₂ Me Me H H 0 H H CF₃ PhC(═O)NHMe Me Me H H 0 H H CF₃ Ph C(═O)N(Me)₂ Me Me H H 0 H H CF₃ PhImidazol-1-yl Me Me H H 0 H H CF₃ Ph Pyrazol-1-yl Me Me H H 0 H H CF₃ Ph1,2,4-Triazol-1-yl Me Me H H 0 H H CF₃ Ph 1,2,4-Triazol-4-yl Me Me H H 0H H CF₃ Ph Tetrazol-1-yl Me Me H H 0 H H CF₃ Ph Tetrazol-5-yl Me Me H H0 H H CF₃ Ph (4,6-Dimethoxypyrimidin-2-yl)oxy Me Me H H 0 H H CF₃ Ph(4,6-Dimethoxypyrimidin-2-yl) sulfonyl Me Me H H 0 H H CF₂CF₃ Ph Cl MeMe H H 0 H H CF₃ (2-Cl)Ph Cl Me Me H H 0 H H CF₃ (2-F)Ph Cl Me Me H H 0H H CF₃ (2-OMe)Ph Cl Me Me H H 0 H H CF₃ (2-Me)Ph Cl Me Me H H 0 H H CF₃(2-NO₂)Ph Cl Me Me H H 0 H H CF₃ (2-CN)Ph Cl Me Me H H 0 H H CF₃(2-C(═O)Me)Ph Cl Me Me H H 0 H H CF₃ (2-C(═O)OMe)Ph Cl Me Me H H 0 H HCF₃ (2-C(═O)OEt)Ph Cl Me Me H H 0 H H CF₃ (2-C(═O)OPr-i)Ph Cl Me Me H H0 H H CF₃ (2-C(═O)NH₂)Ph Cl Me Me H H 0 H H CF₃ (2-C(═O)NHMe)Ph Cl Me MeH H 0 H H CF₃ (2-C(═O)NMe₂)Ph Cl Me Me H H 0 H H CF₃ (3-Cl)Ph Cl Me Me HH 0 H H CF₃ (3-F)Ph Cl Me Me H H 0 H H CF₃ (3-OMe)Ph Cl Me Me H H 0 H HCF₃ (3-Me)Ph Cl Me Me H H 0 H H CF₃ (3-NO₂)Ph Cl Me Me H H 0 H H CF₃(3-CN)Ph Cl Me Me H H 0 H H CF₃ (3-C(═O)Me)Ph Cl Me Me H H 0 H H CF₃(3-C(═O)OMe)Ph Cl Me Me H H 0 H H CF₃ (3-C(═O)OEt)Ph Cl Me Me H H 0 H HCF₃ (3-C(═O)OPr-i)Ph Cl Me Me H H 0 H H CF₃ (3-C(═O)NH₂)Ph Cl Me Me H H0 H H CF₃ (3-C(═O)NHMe)Ph Cl Me Me H H 0 H H CF₃ (3-C(═O)NMe₂)Ph Cl MeMe H H 0 H H CF₃ (4-Cl)Ph Cl Me Me H H 0 H H CF₃ (4-F)Ph Cl Me Me H H 0H H CF₃ (4-OMe)Ph Cl Me Me H H 0 H H CF₃ (4-Me)Ph Cl Me Me H H 0 H H CF₃(4-NO₂)Ph Cl Me Me H H 0 H H CF₃ (4-N)Ph Cl Me Me H H 0 H H CF₃(4-C(═O)Me)Ph Cl Me Me H H 0 H H CF₃ (4-C(═O)OMe)Ph Cl Me Me H H 0 H HCF₃ (4-C(═O)OEt)Ph Cl Me Me H H 0 H H CF₃ (4-C(═O)OPr-i)Ph Cl Me Me H H0 H H CF₃ (4-C(═O)NH₂)Ph Cl Me Me H H 0 H H CF₃ (4-C(═O)NHMe)Ph Cl Me MeH H 0 H H CF₃ C4-C(═O)NMe₂)Ph Cl Me Me H H 0 H H CF₃ Pyrmidin-2-yl Cl MeMe H H 0 H H CF₃ 4,6-Dimethoxypyrmidin-2-yl Cl Me Me H H 0 H H CF₃Thiophen-2-yl Cl Me Me H H 0 H H CF₃ Furan-2-yl Cl Me Me H H 0 H H CF₃SO₂Me Cl Me Me H H 0 H H CF₃ SO₂Et Cl Me Me H H 0 H H CF₃ SO₂Pr-i Cl MeMe H H 0 H H CF₃ SO₂CH₂Ph Cl Me Me H H 0 H H CF₃ SO₂CHF₂ Cl Me Me H H 0H H CF₃ SO₂CF₃ Cl Me Me H H 0 H H CF₃ SO₂Ph Cl Me Me H H 0 H H CF₃C(═O)Me Cl Me Me H H 0 H H CF₃ C(═O)Et Cl Me Me H H 0 H H CF₃ C(═O)Pr-iCl Me Me H H 0 H H CF₃ C(═O)Bu-t Cl Me Me H H 0 H H CF₃ C(═O)Ph Cl Me MeH H 0 H H CF₃ C(═O)CH₂Ph Cl Me Me H H 0 H H CF₃ C(═O)CH₂Cl Cl Me Me H H0 H H CF₃ C(═O)CHCl₂ Cl Me Me H H 0 H H CF₃ C(═O)CF₃ Cl Me Me H H 0 H HCF₃ C(═O)OMe Cl Me Me H H 0 H H CF₃ C(═O)OPh Cl Me Me H H 0 H H CF₃C(═O)OCH₂Ph Cl Me Me H H 0 H H CF₃ C(═O)NHMe Cl Me Me H H 0 H H CF₃C(═O)N(Me)₂ Cl Me Me H H 0 H H CF₃ C(═O)NHPh Cl Me Me H H 0 H H CF₃ NH₂Cl Me Me H H 0 H H Cl —(CH₂)₂O— Me Me H H 0 H H Cl —(CH₂)₃O— Me Me H H 0H H Cl —(CH₂)₃S— Me Me H H 0 H H Cl —(CH₂)₃SO₂— Me Me H H 0 H H CF₃—(CH₂)₂O— Me Me H H 0 H H CF₃ —(CH₂)₃O— Me Me H H 0 H H CF₃ —(CH₂)₃S— MeMe H H 0 H H CF₃ —(CH₂)₃SO₂— Me Me H H 0 H H OMe —(CH₂)₄— Me Me H H 0 HH OCHF₂ —(CH₂)₄— H H H H 0 H H CF₃ Me Cl Me H H H 0 H H CF₃ Me Cl Me HMe H 0 H H CF₃ Me Cl Me Me Me H 0 H H CF₃ Me Cl Me Me H H 0 Me H CF₃ MeCl Me Me H H 0 Et H CF₃ Me Cl Me Me H H 0 Pr-i H CF₃ Me Cl Me Me H H 0Me Me CF₃ Me Cl Me Et H H 0 H H CF₃ Me Cl Et Et H H 0 H H CF₃ Me Cl MePr-i H H 0 H H CF₃ Me Cl Me Pr H H 0 H H CF₃ Me Cl Me Pr-c H H 0 H H CF₃Me Cl Me CH₂Pr-c H H 0 H H CF₃ Me Cl —(CH₂)₂— H H 0 H H CF₃ Me Cl—(CH₂)₃— H H 0 H H CF₃ Me Cl —(CH₂)₄— H H 0 H H CF₃ Me Cl —(CH₂)₅— H H 0H H CF₃ Me Cl H —(CH₂)₃— H 0 H H CF₃ Me Cl H —(CH₂)₄— H 0 H H CF₃ Me ClH —(CH₂)₅— H 0 H H CF₃ Me Cl H —(CH₂)₆— H 0 H H CF₃ Me Cl Me Et H H 2 HH H H H

TABLE 4

R¹ R² R³ R⁴ n R⁵ R⁶ Z³ R³¹ R³² Me Me H H 2 H H O Me F Me Me H H 2 H H OMe Cl Me Me H H 2 H H O Me OMe Me Me H H 2 H H O Me OEt Me Me H H 2 H HO Me OPr-i Me Me H H 2 H H O Me OPh Me Me H H 2 H H O Me OCHF₂ Me Me H H2 H H O Me Me Me Me H H 2 H H O Me CF₃ Me Me H H 2 H H O Me CN Me Me H H2 H H O OCHF₂ F Me Me H H 2 H H O OCHF₂ Cl Me Me H H 2 H H O OCHF₂ Me MeMe H H 2 H H O OCHF₂ CF₃ Me Me H H 2 H H O OCHF₂ CN Me Me H H 2 H H OCF₃ F Me Me H H 2 H H O CF₃ Cl Me Me H H 2 H H O CF₃ OMe Me Me H H 2 H HO CF₃ OEt Me Me H H 2 H H O CF₃ OPr-i Me Me H H 2 H H O CF₃ OPh Me Me HH 2 H H O CF₃ OCHF₂ Me Me H H 2 H H O CF₃ SMe Me Me H H 2 H H O CF₃ SOMeMe Me H H 2 H H O CF₃ SO₂Me Me Me H H 2 H H O CF₃ SEt Me Me H H 2 H H OCF₃ SOEt Me Me H H 2 H H O CF₃ SO₂Et Me Me H H 2 H H O CF₃ SPr-i Me Me HH 2 H H O CF₃ SOPr-i Me Me H H 2 H H O CF₃ SO₂Pr-i Me Me H H 2 H H O CF₃SPh Me Me H H 2 H H O CF₃ SOPh Me Me H H 2 H H O CF₃ SO₂Ph Me Me H H 2 HH O CF₃ SCHF₂ Me Me H H 2 H H O CF₃ SOCHF₂ Me Me H H 2 H H O CF₃ SO₂CHF₂Me Me H H 2 H H O CF₃ SCF₃ Me Me H H 2 H H O CF₃ SOCF₃ Me Me H H 2 H H OCF₃ SO₂CF₃ Me Me H H 2 H H O CF₃ NH₂ Me Me H H 2 H H O CF₃ NHC(═O)Me MeMe H H 2 H H O CF₃ NHC(═O)Ph Me Me H H 2 H H O CF₃ NHC(═O)CH₂Ph Me Me HH 2 H H O CF₃ NHC(═O)CF₃ Me Me H H 2 H H O CF₃ NHSO₂Me Me Me H H 2 H H OCF₃ NHSO₂Ph Me Me H H 2 H H O CF₃ NHSO₂CHF₂ Me Me H H 2 H H O CF₃NHSO₂CF₃ Me Me H H 2 H H O CF₃ NHMe Me Me H H 2 H H O CF₃ NHPh Me Me H H2 H H O CF₃ N(Me)C(═O)Me Me Me H H 2 H H O CF₃ N(Me)C(═O)Ph Me Me H H 2H H O CF₃ N(Me)C(═O)CH₂Ph Me Me H H 2 H H O CF₃ N(Me)C(═O)CF₃ Me Me H H2 H H O CF₃ N(Me)SO₂Me Me Me H H 2 H H O CF₃ N(Me)SO₂Ph Me Me H H 2 H HO CF₃ N(Me)SO₂CHF₂ Me Me H H 2 H H O CF₃ N(Me)SO₂CF₃ Me Me H H 2 H H OCF₃ N(Me)₂ Me Me H H 2 H H O CF₃ N(Me)Ph Me Me H H 2 H H O CF₃ Me Me MeH H 2 H H O CF₃ CF₃ Me Me H H 2 H H O CF₃ CN Me Me H H 2 H H O Ph Me H HH H 2 H H O CF₃ Me Me H H H 2 H H O CF₃ Me Me H Me H 2 H H O CF₃ Me MeMe Me H 2 H H O CF₃ Me Me Me H H 2 Me H O CF₃ Me Me Me H H 2 Et H O CF₃Me Me Me H H 2 Pr-i H O CF₃ Me Me Me H H 2 Me Me O CF₃ Me Me Et H H 2 HH O CF₃ Me Et Et H H 2 H H O CF₃ Me Me Pr-i H H 2 H H O CF₃ Me Me Pr H H2 H H O CF₃ Me Me Pr-c H H 2 H H O CF₃ Me Me CH₂Pr-c H H 2 H H O CF₃ Me—(CH₂)₂— H H 2 H H O CF₃ Me —(CH₂)₃— H H 2 H H O CF₃ Me —(CH₂)₄— H H 2 HH O CF₃ Me —(CH₂)₅— H H 2 H H O CF₃ Me H —(CH₂)₃— H 2 H H O CF₃ Me H—(CH₂)₄— H 2 H H O CF₃ Me H —(CH₂)₅— H 2 H H O CF₃ Me H —(CH₂)₆— H 2 H HO CF₃ Me Me Me H H 2 H H S Me F Me Me H H 2 H H S Me Cl Me Me H H 2 H HS Me OMe Me Me H H 2 H H S Me OEt Me Me H H 2 H H S Me OPr-i Me Me H H 2H H S Me OPh Me Me H H 2 H H S Me OCHF₂ Me Me H H 2 H H S OCHF₂ F Me MeH H 2 H H S OCHF₂ Cl Me Me H H 2 H H S OCHF₂ Me Me Me H H 2 H H S OCHF₂CF₃ Me Me H H 2 H H S OCHF₂ CN Me Me H H 2 H H S CF₃ F Me Me H H 2 H H SCF₃ Cl Me Me H H 2 H H S CF₃ OMe Me Me H H 2 H H S CF₃ OEt Me Me H H 2 HH S CF₃ OPh Me Me H H 2 H H S CF₃ OCHF₂ Me Me H H 2 H H S CF₃ SMe Me MeH H 2 H H S CF₃ SOMe Me Me H H 2 H H S CF₃ SO₂Me Me Me H H 2 H H S CF₃SEt Me Me H H 2 H H S CF₃ SOEt Me Me H H 2 H H S CF₃ SO₂Et Me Me H H 2 HH S CF₃ SPr-i Me Me H H 2 H H S CF₃ SOPr-i Me Me H H 2 H H S CF₃ SO₂Pr-iMe Me H H 2 H H S CF₃ SPh Me Me H H 2 H H S CF₃ SOPh Me Me H H 2 H H SCF₃ SO₂Ph Me Me H H 2 H H S CF₃ SCHF₂ Me Me H H 2 H H S CF₃ SOCHF₂ Me MeH H 2 H H S CF₃ SO₂CHF₂ Me Me H H 2 H H S CF₃ SCF₃ Me Me H H 2 H H S CF₃SOCF₃ Me Me H H 2 H H S CF₃ SO₂CF₃ Me Me H H 2 H H S CF₃ NH₂ Me Me H H 2H H S CF₃ NHC(═O)Me Me Me H H 2 H H S CF₃ NHC(═O)Ph Me Me H H 2 H H SCF₃ NHC(═O)CH₂Ph Me Me H H 2 H H S CF₃ NHC(═O)CF₃ Me Me H H 2 H H S CF₃NHSO₂Me Me Me H H 2 H H S CF₃ NHSO₂Ph Me Me H H 2 H H S CF₃ NHSO₂CHF₂ MeMe H H 2 H H S CF₃ NHSO₂CF₃ Me Me H H 2 H H S CF₃ NHMe Me Me H H 2 H H SCF₃ NHPh Me Me H H 2 H H S CF₃ N(Me)C(═O)Me Me Me H H 2 H H S CF₃N(Me)C(═O)Ph Me Me H H 2 H H S CF₃ N(Me)C(═O)CH₂Ph Me Me H H 2 H H S CF₃N(Me)C(═O)CF₃ Me Me H H 2 H H S CF₃ N(Me)SO₂Me Me Me H H 2 H H S CF₃N(Me)SO₂Ph Me Me H H 2 H H S CF₃ N(Me)SO₂CHF₂ Me Me H H 2 H H S CF₃N(Me)SO₂CF₃ Me Me H H 2 H H S CF₃ N(Me)₂ Me Me H H 2 H H S CF₃ N(Me)PhMe Me H H 2 H H S CF₃ Me Me Me H H 2 H H S CF₃ CN H H H H 2 H H S CF₃ ClMe H H H 2 H H S CF₃ Cl Me H Me H 2 H H S CF₃ Cl Me Me Me H 2 H H S CF₃Cl Me Me H H 2 Me H S CF₃ Cl Me Me H H 2 Et H S CF₃ Cl Me Me H H 2 Pr-iH S CF₃ Cl Me Me H H 2 Me Me S CF₃ Cl Me Et H H 2 H H S CF₃ Cl Et Et H H2 H H S CF₃ Cl Me Pr-i H H 2 H H S CF₃ Cl Me Pr H H 2 H H S CF₃ Cl MePr-c H H 2 H H S CF₃ Cl Me CH₂Pr-c H H 2 H H S CF₃ Cl —(CH₂)₂— H H 2 H HS CF₃ Cl —(CH₂)₃— H H 2 H H S CF₃ Cl —(CH₂)₄— H H 2 H H S CF₃ Cl—(CH₂)₅— H H 2 H H S CF₃ Cl H —(CH₂)₃— H 2 H H S CF₃ Cl H —(CH₂)₄— H 2 HH S CF₃ Cl H —(CH₂)₅— H 2 H H S CF₃ Cl H —(CH₂)₆— H 2 H H S CF₃ Cl Me MeH H 1 H H O Me F Me Me H H 1 H H O Me Cl Me Me H H 1 H H O Me OMe Me MeH H 1 H H O Me OEt Me Me H H 1 H H O Me OPr-i Me Me H H 1 H H O Me OPhMe Me H H 1 H H O Me OCHF₂ Me Me H H 1 H H O Me Me Me Me H H 1 H H O MeCF₃ Me Me H H 1 H H O Me CN Me Me H H 1 H H O OCHF₂ F Me Me H H 1 H H OOCHF₂ Cl Me Me H H 1 H H O OCHF₂ Me Me Me H H 1 H H O OCHF₂ CF₃ Me Me HH 1 H H O OCHF₂ CN Me Me H H 1 H H O CF₃ F Me Me H H 1 H H O CF₃ Cl MeMe H H 1 H H O CF₃ OMe Me Me H H 1 H H O CF₃ OEt Me Me H H 1 H H O CF₃OPr-i Me Me H H 1 H H O CF₃ OPh Me Me H H 1 H H O CF₃ OCHF₂ Me Me H H 1H H O CF₃ SMe Me Me H H 1 H H O CF₃ SO₂Me Me Me H H 1 H H O CF₃ SEt MeMe H H 1 H H O CF₃ SO₂Et Me Me H H 1 H H O CF₃ SPr-i Me Me H H 1 H H OCF₃ SO₂Pr-i Me Me H H 1 H H O CF₃ SPh Me Me H H 1 H H O CF₃ SO₂Ph Me MeH H 1 H H O CF₃ SCHF₂ Me Me H H 1 H H O CF₃ SO₂CHF₂ Me Me H H 1 H H OCF₃ SCF₃ Me Me H H 1 H H O CF₃ SO₂CF₃ Me Me H H 1 H H O CF₃ NH₂ Me Me HH 1 H H O CF₃ NHC(═O)Me Me Me H H 1 H H O CF₃ NHC(═O)Ph Me Me H H 1 H HO CF₃ NHC(═O)CH₂Ph Me Me H H 1 H H O CF₃ NHC(═O)CF₃ Me Me H H 1 H H OCF₃ NHSO₂Me Me Me H H 1 H H O CF₃ NHSO₂Ph Me Me H H 1 H H O CF₃NHSO₂CHF₂ Me Me H H 1 H H O CF₃ NHSO₂CF₃ Me Me H H 1 H H O CF₃ NHMe MeMe H H 1 H H O CF₃ NHPh Me Me H H 1 H H O CF₃ N(Me)C(═O)Me Me Me H H 1 HH O CF₃ N(Me)C(═O)Ph Me Me H H 1 H H O CF₃ N(Me)C(═O)CH₂Ph Me Me H H 1 HH O CF₃ N(Me)C(═O)CF₃ Me Me H H 1 H H O CF₃ N(Me)SO₂Me Me Me H H 1 H H OCF₃ N(Me)SO₂Ph Me Me H H 1 H H O CF₃ N(Me)SO₂CHF₂ Me Me H H 1 H H O CF₃N(Me)SO₂CF₃ Me Me H H 1 H H O CF₃ N(Me)₂ Me Me H H 1 H H O CF₃ N(Me)PhMe Me H H 1 H H O CF₃ Me Me Me H H 1 H H O CF₃ CF₃ Me Me H H 1 H H O CF₃CN Me Me H H 1 H H O Ph Me H H H H 1 H H O CF₃ Me Me H H H 1 H H O CF₃Me Me H Me H 1 H H O CF₃ Me Me Me Me H 1 H H O CF₃ Me Me Me H H 1 Me H OCF₃ Me Me Me H H 1 Et H O CF₃ Me Me Me H H 1 Pr-i H O CF₃ Me Me Me H H 1Me Me O CF₃ Me Me Et H H 1 H H O CF₃ Me Et Et H H 1 H H O CF₃ Me Me Pr-iH H 1 H H O CF₃ Me Me Pr H H 1 H H O CF₃ Me Me Pr-c H H 1 H H O CF₃ MeMe CH₂Pr-c H H 1 H H O CF₃ Me —(CH₂)₂— H H 1 H H O CF₃ Me —(CH₂)₃— H H 1H H O CF₃ Me —(CH₂)₄— H H 1 H H O CF₃ Me —(CH₂)₅— H H 1 H H O CF₃ Me H—(CH₂)₃— H 1 H H O CF₃ Me H —(CH₂)₄— H 1 H H O CF₃ Me H —(CH₂)₅— H 1 H HO CF₃ Me H —(CH₂)₆— H 1 H H O CF₃ Me Me Me H H 1 H H S Me F Me Me H H 1H H S Me Cl Me Me H H 1 H H S Me OMe Me Me H H 1 H H S Me OEt Me Me H H1 H H S Me OPr-i Me Me H H 1 H H S Me OPh Me Me H H 1 H H S Me OCHF₂ MeMe H H 1 H H S OCHF₂ F Me Me H H 1 H H S OCHF₂ Cl Me Me H H 1 H H SOCHF₂ Me Me Me H H 1 H H S OCHF₂ CF₃ Me Me H H 1 H H S OCHF₂ CN Me Me HH 1 H H S CF₃ F Me Me H H 1 H H S CF₃ Cl Me Me H H 1 H H S CF₃ OMe Me MeH H 1 H H S CF₃ OEt Me Me H H 1 H H S CF₃ OPh Me Me H H 1 H H S CF₃OCHF₂ Me Me H H 1 H H S CF₃ SMe Me Me H H 1 H H S CF₃ SO₂Me Me Me H H 1H H S CF₃ SEt Me Me H H 1 H H S CF₃ SO₂Et Me Me H H 1 H H S CF₃ SPr-i MeMe H H 1 H H S CF₃ SO₂Pr-i Me Me H H 1 H H S CF₃ SPh Me Me H H 1 H H SCF₃ SO₂Ph Me Me H H 1 H H S CF₃ SCHF₂ Me Me H H 1 H H S CF₃ SO₂CHF₂ MeMe H H 1 H H S CF₃ SCF₃ Me Me H H 1 H H S CF₃ SO₂CF₃ Me Me H H 1 H H SCF₃ NH₂ Me Me H H 1 H H S CF₃ NHC(═O)Me Me Me H H 1 H H S CF₃ NHC(═O)PhMe Me H H 1 H H S CF₃ NHC(═O)CH₂Ph Me Me H H 1 H H S CF₃ NHC(═O)CF₃ MeMe H H 1 H H S CF₃ NHSO₂Me Me Me H H 1 H H S CF₃ NHSO₂Ph Me Me H H 1 H HS CF₃ NHSO₂CHF₂ Me Me H H 1 H H S CF₃ NHSO₂CF₃ Me Me H H 1 H H S CF₃NHMe Me Me H H 1 H H S CF₃ NHPh Me Me H H 1 H H S CF₃ N(Me)C(═O)Me Me MeH H 1 H H S CF₃ N(Me)C(═O)Ph Me Me H H 1 H H S CF₃ N(Me)C(═O)CH₂Ph Me MeH H 1 H H S CF₃ N(Me)C(═O)CF₃ Me Me H H 1 H H S CF₃ N(Me)SO₂Me Me Me H H1 H H S CF₃ N(Me)SO₂Ph Me Me H H 1 H H S CF₃ N(Me)SO₂CHF₂ Me Me H H 1 HH S CF₃ N(Me)SO₂CF₃ Me Me H H 1 H H S CF₃ N(Me)₂ Me Me H H 1 H H S CF₃N(Me)Ph Me Me H H 1 H H S CF₃ Me Me Me H H 1 H H S CF₃ CN H H H H 1 H HS CF₃ Cl Me H H H 1 H H S CF₃ Cl Me H Me H 1 H H S CF₃ Cl Me Me Me H 1 HH S CF₃ Cl Me Me H H 1 Me H S CF₃ Cl Me Me H H 1 Et H S CF₃ Cl Me Me H H1 Pr-i H S CF₃ Cl Me Me H H 1 Me Me S CF₃ Cl Me Et H H 1 H H S CF₃ Cl EtEt H H 1 H H S CF₃ Cl Me Pr-i H H 1 H H S CF₃ Cl Me Pr H H 1 H H S CF₃Cl Me Pr-c H H 1 H H S CF₃ Cl Me CH₂Pr-c H H 1 H H S CF₃ Cl —(CH₂)₂— H H1 H H S CF₃ Cl —(CH₂)₃— H H 1 H H S CF₃ Cl —(CH₂)₄— H H 1 H H S CF₃ Cl—(CH₂)₅— H H 1 H H S CF₃ Cl H —(CH₂)₃— H 1 H H S CF₃ Cl H —(CH₂)₄— H 1 HH S CF₃ Cl H —(CH₂)₅— H 1 H H S CF₃ Cl H —(CH₂)₆— H 1 H H S CF₃ Cl Me MeH H 0 H H O Me F Me Me H H 0 H H O Me Cl Me Me H H 0 H H O Me OMe Me MeH H 0 H H O Me OEt Me Me H H 0 H H O Me OPr-i Me Me H H 0 H H O Me OPhMe Me H H 0 H H O Me OCHF₂ Me Me H H 0 H H O Me Me Me Me H H 0 H H O MeCF₃ Me Me H H 0 H H O Me CN Me Me H H 0 H H O OCHF₂ F Me Me H H 0 H H OOCHF₂ Cl Me Me H H 0 H H O OCHF₂ Me Me Me H H 0 H H O OCHF₂ CF₃ Me Me HH 0 H H O OCHF₂ CN Me Me H H 0 H H O CF₃ F Me Me H H 0 H H O CF₃ Cl MeMe H H 0 H H O CF₃ OMe Me Me H H 0 H H O CF₃ OEt Me Me H H 0 H H O CF₃OPr-i Me Me H H 0 H H O CF₃ OPh Me Me H H 0 H H O CF₃ OCHF₂ Me Me H H 0H H O CF₃ SMe Me Me H H 0 H H O CF₃ SO₂Me Me Me H H 0 H H O CF₃ SEt MeMe H H 0 H H O CF₃ SO₂Et Me Me H H 0 H H O CF₃ SPr-i Me Me H H 0 H H OCF₃ SO₂Pr-i Me Me H H 0 H H O CF₃ SPh Me Me H H 0 H H O CF₃ SO₂Ph Me MeH H 0 H H O CF₃ SCHF₂ Me Me H H 0 H H O CF₃ SO₂CHF₂ Me Me H H 0 H H OCF₃ SCF₃ Me Me H H 0 H H O CF₃ SO₂CF₃ Me Me H H 0 H H O CF₃ NH₂ Me Me HH 0 H H O CF₃ NHC(═O)Me Me Me H H 0 H H O CF₃ NHC(═O)Ph Me Me H H 0 H HO CF₃ NHC(═O)CH₂Ph Me Me H H 0 H H O CF₃ NHC(═O)CF₃ Me Me H H 0 H H OCF₃ NHSO₂Me Me Me H H 0 H H O CF₃ NHSO₂Ph Me Me H H 0 H H O CF₃NHSO₂CHF₂ Me Me H H 0 H H O CF₃ NHSO₂CF₃ Me Me H H 0 H H O CF₃ NHMe MeMe H H 0 H H O CF₃ NHPh Me Me H H 0 H H O CF₃ N(Me)C(═0)Me Me Me H H 0 HH O CF₃ N(Me)C(═O)Ph Me Me H H 0 H H O CF₃ N(Me)C(═0)CH₂Ph Me Me H H 0 HH O CF₃ N(Me)C(═O)CF₃ Me Me H H 0 H H O CF₃ N(Me)SO₂Me Me Me H H 0 H H OCF₃ N(Me)SO₂Ph Me Me H H 0 H H O CF₃ N(Me)SO₂CHF₂ Me Me H H 0 H H O CF₃N(Me)SO₂CF₃ Me Me H H 0 H H O CF₃ N(Me)₂ Me Me H H 0 H H O CF₃ N(Me)PhMe Me H H 0 H H O CF₃ Me Me Me H H 0 H H O CF₃ CF₃ Me Me H H 0 H H O CF₃CN Me Me H H 0 H H O Ph Me H H H H 0 H H O CF₃ Me Me H H H 0 H H O CF₃Me Me H Me H 0 H H O CF₃ Me Me Me Me H 0 H H O CF₃ Me Me Me H H 0 Me H OCF₃ Me Me Me H H 0 Et H O CF₃ Me Me Me H H 0 Pr-i H O CF₃ Me Me Me H H 0Me Me O CF₃ Me Me Et H H 0 H H O CF₃ Me Et Et H H 0 H H O CF₃ Me Me Pr-iH H 0 H H O CF₃ Me Me Pr H H 0 H H O CF₃ Me Me Pr-c H H 0 H H O CF₃ MeMe CH₂Pr-c H H 0 H H O CF₃ Me —(CH₂)₂— H H 0 H H O CF₃ Me —(CH₂)₃— H H 0H H O CF₃ Me —(CH₂)₄— H H 0 H H O CF₃ Me —(CH₂)₅— H H 0 H H O CF₃ Me H—(CH₂)₃— H 0 H H O CF₃ Me H —(CH₂)₄— H 0 H H O CF₃ Me H —(CH₂)₅— H 0 H HO CF₃ Me H —(CH₂)₆— H 0 H H O CF₃ Me Me Me H H 0 H H S Me F Me Me H H 0H H S Me Cl Me Me H H 0 H H S Me OMe Me Me H H 0 H H S Me OEt Me Me H H0 H H S Me OPr-i Me Me H H 0 H H S Me OPh Me Me H H 0 H H S Me OCHF₂ MeMe H H 0 H H S OCHF₂ F Me Me H H 0 H H S OCHF₂ Cl Me Me H H 0 H H SOCHF₂ Me Me Me H H 0 H H S OCHF₂ CF₃ Me Me H H 0 H H S OCHF₂ CN Me Me HH 0 H H S CF₃ F Me Me H H 0 H H S CF₃ Cl Me Me H H 0 H H S CF₃ OMe Me MeH H 0 H H S CF₃ OEt Me Me H H 0 H H S CF₃ OPh Me Me H H 0 H H S CF₃OCHF₂ Me Me H H 0 H H S CF₃ SMe Me Me H H 0 H H S CF₃ SO₂Me Me Me H H 0H H S CF₃ SEt Me Me H H 0 H H S CF₃ SO₂Et Me Me H H 0 H H S CF₃ SPr-i MeMe H H 0 H H S CF₃ SO₂Pr-i Me Me H H 0 H H S CF₃ SPh Me Me H H 0 H H SCF₃ SO₂Ph Me Me H H 0 H H S CF₃ SCHF₂ Me Me H H 0 H H S CF₃ SO₂CHF₂ MeMe H H 0 H H S CF₃ SCF₃ Me Me H H 0 H H S CF₃ SO₂CF₃ Me Me H H 0 H H SCF₃ NH₂ Me Me H H 0 H H S CF₃ NHC(═O)Me Me Me H H 0 H H S CF₃ NHC(═O)PhMe Me H H 0 H H S CF₃ NHC(═O)CH₂Ph Me Me H H 0 H H S CF₃ NHC(═O)CF₃ MeMe H H 0 H H S CF₃ NHSO₂Me Me Me H H 0 H H S CF₃ NHSO₂Ph Me Me H H 0 H HS CF₃ NHSO₂CHF₂ Me Me H H 0 H H S CF₃ NHSO₂CF₃ Me Me H H 0 H H S CF₃NHMe Me Me H H 0 H H S CF₃ NHPh Me Me H H 0 H H S CF₃ N(Me)C(═O)Me Me MeH H 0 H H S CF₃ N(Me)C(═O)Ph Me Me H H 0 H H S CF₃ N(Me)C(═O)CH₂Ph Me MeH H 0 H H S CF₃ N(Me)C(═O)CF₃ Me Me H H 0 H H S CF₃ N(Me)SO₂Me Me Me H H0 H H S CF₃ N(Me)SO₂Ph Me Me H H 0 H H S CF₃ N(Me)SO₂CHF₂ Me Me H H 0 HH S CF₃ N(Me)SO₂CF₃ Me Me H H 0 H H S CF₃ N(Me)₂ Me Me H H 0 H H S CF₃N(Me)Ph Me Me H H 0 H H S CF₃ Me Me Me H H 0 H H S CF₃ CN H H H H 0 H HS CF₃ Cl Me H H H 0 H H S CF₃ Cl Me H Me H 0 H H S CF₃ Cl Me Me Me H 0 HH S CF₃ Cl Me Me H H 0 Me H S CF₃ Cl Me Me H H 0 Et H S CF₃ Cl Me Me H H0 Pr-i H S CF₃ Cl Me Me H H 0 Me Me S CF₃ Cl Me Et H H 0 H H S CF₃ Cl EtEt H H 0 H H S CF₃ Cl Me Pr-i H H 0 H H S CF₃ Cl Me Pr H H 0 H H S CF₃Cl Me Pr-c H H 0 H H S CF₃ Cl Me CH₂Pr-c H H 0 H H S CF₃ Cl —(CH₂)₂— H H0 H H S CF₃ Cl —(CH₂)₃— H H 0 H H S CF₃ Cl —(CH₂)₄— H H 0 H H S CF₃ Cl—(CH₂)₅— H H 0 H H S CF₃ Cl H —(CH₂)₃— H 0 H H S CF₃ Cl H —(CH₂)₄— H 0 HH S CF₃ Cl H —(CH₂)₅— H 0 H H S CF₃ Cl H —(CH₂)₆— H 0 H H S CF₃ Cl

TABLE 5

R¹ R² R³ R⁴ n R⁵ R⁶ Z⁴ R³³ R³⁴ Me Me H H 2 H H NMe Cl H Me Me H H 2 H HNMe Cl Me Me Me H H 2 H H NMe Cl Et Me Me H H 2 H H NMe Cl CF₃ Me Me H H2 H H NMe CF₃ H Me Me H H 2 H H NMe CF₃ Me Me Me H H 2 H H NMe OCHF₂ HMe Me H H 2 H H NMe OCHF₂ Me Me Me H H 2 H H NMe C(═O)Me H Me Me H H 2 HH NMe C(═O)Me Me Me Me H H 2 H H NMe —(CH₂)₃— Me Me H H 2 H H NMe—(CH₂)₄— Me Me H H 2 H H NEt Cl Me Me Me H H 2 H H NEt CF₃ H Me Me H H 2H H NEt CF₃ Me Me Me H H 2 H H NEt OCHF₂ H Me Me H H 2 H H NEt OCHF₂ MeMe Me H H 2 H H NEt —(CH₂)₃— Me Me H H 2 H H NEt —(CH₂)₄— Me Me H H 2 HH NPr-i Cl Me Me Me H H 2 H H NPr-i CF₃ H Me Me H H 2 H H NPr-i CF₃ MeMe Me H H 2 H H NPr-i OCHF₂ H Me Me H H 2 H H NPr-i OCHF₂ Me Me Me H H 2H H NPr-i —(CH₂)₃— Me Me H H 2 H H NPr-i —(CH₂)₄— Me Me H H 2 H H NPr ClMe Me Me H H 2 H H NPr CF₃ H Me Me H H 2 H H NPr CF₃ Me Me Me H H 2 H HNPr OCHF₂ H Me Me H H 2 H H NPr OCHF₂ Me Me Me H H 2 H H NPr —(CH₂)₃— MeMe H H 2 H H NPr —(CH₂)₄— Me Me H H 2 H H NBu-t Cl Me Me Me H H 2 H HNBu-t CF₃ H Me Me H H 2 H H NBu-t CF₃ Me Me Me H H 2 H H NBu-t OCHF₂ HMe Me H H 2 H H NBu-t OCHF₂ Me Me Me H H 2 H H NBu-t —(CH₂)₃— Me Me H H2 H H NBu-t —(CH₂)₄— Me Me H H 2 H H NCH₂Ph Cl Me Me Me H H 2 H H NCH₂PhCF₃ H Me Me H H 2 H H NCH₂Ph OCHF₂ H Me Me H H 2 H H NCH₂OMe Cl Me Me MeH H 2 H H NCH₂OMe CF₃ H Me Me H H 2 H H NCH₂OMe OCHF₂ H Me Me H H 2 H HNCH₂C≡CH Cl Me Me Me H H 2 H H NCH₂C≡CH CF₃ H Me Me H H 2 H H NCH₂C≡CHOCHF₂ H Me Me H H 2 H H NCH₂CH═CH₂ Cl Me Me Me H H 2 H H NCH₂CH═CH₂ CF₃H Me Me H H 2 H H NCH₂CH═CH₂ OCHF₂ H Me Me H H 2 H H NCHF₂ Cl Me Me Me HH 2 H H NCHF₂ CF₃ H Me Me H H 2 H H NCHF₂ CF₃ Me Me Me H H 2 H H NCHF₂OCHF₂ H Me Me H H 2 H H NCHF₂ OCHF₂ Me Me Me H H 2 H H NCHF₂ C(═O)Me HMe Me H H 2 H H NCHF₂ C(═O)Me Me Me Me H H 2 H H NCHF₂ —(CH₂)₃— Me Me HH 2 H H NCHF₂ —(CH₂)₄— Me Me H H 2 H H NPh OMe Me Me Me H H 2 H H NPhOEt Me Me Me H H 2 H H NPh OCHF₂ Me Me Me H H 2 H H NPh OCH₂CF₃ Me Me MeH H 2 H H NPh CF₃ H Me Me H H 2 H H NPh OCH₂CH═CH₂ Me Me Me H H 2 H HNPh OCH₂CH≡CH Me Me Me H H 2 H H NPh Cl Me Me Me H H 2 H H N(2-Cl)Ph ClMe Me Me H H 2 H H N(2-F)Ph Cl Me Me Me H H 2 H H N(2-OMe)Ph Cl Me Me MeH H 2 H H N(2-Me)Ph Cl Me Me Me H H 2 H H N(3-Cl)Ph Cl Me Me Me H H 2 HH N(3-F)Ph Cl Me Me Me H H 2 H H N(3-OMe)Ph Cl Me Me Me H H 2 H HN(3-Me)Ph Cl Me Me Me H H 2 H H N(4-Cl)Ph Cl Me Me Me H H 2 H H N(4-F)PhCl Me Me Me H H 2 H H N(4-OMe)Ph Cl Me Me Me H H 2 H H N(4-Me)Ph Cl MeMe Me H H 2 H H N(Thiophen-2-yl) Cl Me Me Me H H 2 H H N(Thiophen-2-yl)CF₃ H Me Me H H 2 H H N(Thiophen-2-yl) OCHF₂ H Me Me H H 2 H H NC(═O)MeCl Me Me Me H H 2 H H NC(═O)Me CF₃ H Me Me H H 2 H H NC(═O)Me OCHF₂ H MeMe H H 2 H H NC(═O)CF₃ Cl Me Me Me H H 2 H H NC(═O)CF₃ CF₃ H Me Me H H 2H H NC(═O)CF₃ OCHF₂ H Me Me H H 2 H H NC(═O)CH₂Ph Cl Me Me Me H H 2 H HNC(═O)CH₂Ph CF₃ H Me Me H H 2 H H NC(═O)CH₂Ph OCHF₂ H Me Me H H 2 H HNC(═O)Ph Cl Me Me Me H H 2 H H NC(═O)Ph CF₃ H Me Me H H 2 H H NC(═O)PhOCHF₂ H Me Me H H 2 H H NC(═O)OMe Cl Me Me Me H H 2 H H NC(═O)OMe CF₃ HMe Me H H 2 H H NC(═O)OMe OCHF₂ H Me Me H H 2 H H NC(═O)OCH₂Ph Cl Me MeMe H H 2 H H NC(═O)OCH₂Ph CF₃ H Me Me H H 2 H H NC(═O)OCH₂Ph OCHF₂ H MeMe H H 2 H H NC(═O)OPh Cl Me Me Me H H 2 H H NC(═O)OPh CF₃ H Me Me H H 2H H NC(═O)OPh OCHF₂ H Me Me H H 2 H H NC(═O)NHMe Cl Me Me Me H H 2 H HNC(═O)NHMe CF₃ H Me Me H H 2 H H NC(═O)NHMe OCHF₂ H Me Me H H 2 H HNC(═O)N(Me)₂ Cl Me Me Me H H 2 H H NC(═O)N(Me)₂ CF₃ H Me Me H H 2 H HNC(═O)N(Me)₂ OCHF₂ H H H H H 2 H H NPh Cl Me Me H H H 2 H H NPh Cl Me MeH Me H 2 H H NPh Cl Me Me Me H H 2 Me H NPh Cl Me Me Me H H 2 Et H NPhCl Me Me Me H H 2 Pr-i H NPh Cl Me Me Me H H 2 Me Me NPh Cl Me Me Et H H2 H H NPh Cl Me Et Et H H 2 H H NPh Cl Me Me Pr-i H H 2 H H NPh Cl Me MePr H H 2 H H NPh Cl Me Me Pr-c H H 2 H H NPh Cl Me Me CH₂Pr-c H H 2 H HNPh Cl Me —(CH₂)₂— H H 2 H H NPh Cl Me —(CH₂)₃— H H 2 H H NPh Cl Me—(CH₂)₄— H H 2 H H NPh Cl Me —(CH₂)₅— H H 2 H H NPh Cl Me H —(CH₂)₃— H 2H H NPh Cl Me H —(CH₂)₄— H 2 H H NPh Cl Me H —(CH₂)₅— H 2 H H NPh Cl MeH —(CH₂)₆— H 2 H H NPh Cl Me Me Me H H 2 H H O H Me Me Me H H 2 H H O ClMe Me Me H H 2 H H S H Me Me Me H H 2 H H S Cl Me Me Me H H 1 H H NMe ClH Me Me H H 1 H H NMe Cl Me Me Me H H 1 H H NMe Cl Et Me Me H H 1 H HNMe Cl CF₃ Me Me H H 1 H H MAe CF₃ H Me Me H H 1 H H NMe CF₃ Me Me Me HH 1 H H NMe OCHF₂ H Me Me H H 1 H H NMe OCHF₂ Me Me Me H H 1 H H NMeC(═O)Me H Me Me H H 1 H H NMe C(═O)Me Me Me Me H H 1 H H NMe —(CH₂)₃— MeMe H H 1 H H NMe —(CH₂)₄— Me Me H H 1 H H NEt Cl Me Me Me H H 1 H H NEtCF₃ H Me Me H H 1 H H NEt CF₃ Me Me Me H H 1 H H NEt OCHF₂ H Me Me H H 1H H NEt OCHF₂ Me Me Me H H 1 H H NEt —(CH₂)₃— Me Me H H 1 H H NEt—(CH₂)₄— Me Me H H 1 H H NPr-i Cl Me Me Me H H 1 H H NPr-i CF₃ H Me Me HH 1 H H NPr-i CF₃ Me Me Me H H 1 H H NPr-i OCHF₂ H Me Me H H 1 H H NPr-iOCHF₂ Me Me Me H H 1 H H NPr-i —(CH₂)₃— Me Me H H 1 H H NPr-i —(CH₂)₄—Me Me H H 1 H H NPr Cl Me Me Me H H 1 H H NPr CF₃ H Me Me H H I H H NPrCF₃ Me Me Me H H 1 H H NPr OCHF₂ H Me Me H H 1 H H NPr OCHF₂ Me Me Me HH 1 H H NPr —(CH₂)₃— Me Me H H 1 H H NPr —(CH₂)₄— Me Me H H 1 H H NBu-tCl Me Me Me H H 1 H H NBu-t CF₃ H Me Me H H 1 H H NBu-t CF₃ Me Me Me H H1 H H NBu-t OCHF₂ H Me Me H H 1 H H NBu-t OCHF₂ Me Me Me H H 1 H H NBu-t—(CH₂)₃— Me Me H H 1 H H NBu-t —(CH₂)₄— Me Me H H 1 H H NCH₂Ph Cl Me MeMe H H 1 H H NCH₂Ph CF₃ H Me Me H H 1 H H NCH₂Ph OCHF₂ H Me Me H H 1 H HNCH₂OMe Cl Me Me Me H H 1 H H NCH₂OMe CF₃ H Me Me H H 1 H H NCH₂OMeOCHF₂ H Me Me H H 1 H H NCH₂C≡CH Cl Me Me Me H H 1 H H NCH₂C≡CH CF₃ H MeMe H H 1 H H NCH₂C≡CH OCHF₂ H Me Me H H 1 H H NCH₂CH═CH₂ Cl Me Me Me H H1 H H NCH₂CH═CH₂ CF₃ H Me Me H H 1 H H NCH₂CH═CH₂ OCHF₂ H Me Me H H 1 HH NCHF₂ Cl Me Me Me H H 1 H H NCHF₂ CF₃ H Me Me H H 1 H H NCHF₂ CF₃ MeMe Me H H 1 H H NCHF₂ OCHF₂ H Me Me H H 1 H H NCHF₂ OCHF₂ Me Me Me H H 1H H NCHF₂ C(═O)Me H Me Me H H 1 H H NCHF₂ C(═O)Me Me Me Me H H 1 H HNCHF₂ —(CH₂)₃— Me Me H H 1 H H NCHF₂ —(CH₂)₄— Me Me H H 1 H H NPh OMe MeMe Me H H 1 H H NPh OEt Me Me Me H H 1 H H NPh OCHF₂ Me Me Me H H 1 H HNPh OCH₂CF₃ Me Me Me H H 1 H H NPh CF₃ H Me Me H H 1 H H NPh OCH₂CH═CH₂Me Me Me H H 1 H H NPh OCH₂CH≡CH Me Me Me H H 1 H H NPh Cl Me Me Me H H1 H H N(2-Cl)Ph Cl Me Me Me H H 1 H H N(2-F)Ph Cl Me Me Me H H 1 H HN(2-OMe)Ph Cl Me Me Me H H 1 H H N(2-Me)Ph Cl Me Me Me H H 1 H HN(3-Cl)Ph Cl Me Me Me H H 1 H H N(3-F)Ph Cl Me Me Me H H 1 H HN(3-OMe)Ph Cl Me Me Me H H 1 H H N(3-Me)Ph Cl Me Me Me H H 1 H HN(4-Cl)Ph Cl Me Me Me H H 1 H H N(4-F)Ph Cl Me Me Me H H 1 H HN(4-OMe)Ph Cl Me Me Me H H 1 H H N(4-Me)Ph Cl Me Me Me H H 1 H HN(Thiophen-2-yl) Cl Me Me Me H H 1 H H N(Thiophen-2-yl) CF₃ H Me Me H H1 H H N(Thiophen-2-yl) OCHF₂ H Me Me H H 1 H H NC(═O)Me Cl Me Me Me H H1 H H NC(═O)Me CF₃ H Me Me H H 1 H H NC(═O)Me OCHF₂ H Me Me H H 1 H HNC(═O)CF₃ Cl Me Me Me H H 1 H H NC(═O)CF₃ CF₃ H Me Me H H 1 H HNC(═O)CF₃ OCHF₂ H Me Me H H 1 H H NC(═O)CH₂Ph Cl Me Me Me H H 1 H HNC(═O)CH₂Ph CF₃ H Me Me H H 1 H H NC(═O)CH₂Ph OCHF₂ H Me Me H H 1 H HNC(═O)Ph Cl Me Me Me H H 1 H H NC(═O)Ph CF₃ H Me Me H H 1 H H NC(═O)PhOCHF₂ H Me Me H H 1 H H NC(═O)OMe Cl Me Me Me H H 1 H H NC(═O)OMe CF₃ HMe Me H H 1 H H NC(═O)OMe OCHF₂ H Me Me H H 1 H H NC(═O)OCH₂Ph Cl Me MeMe H H 1 H H NC(═O)OCH₂Ph CF₃ H Me Me H H 1 H H NC(═O)OCH₂Ph OCHF₂ H MeMe H H 1 H H NC(═O)OPh Cl Me Me Me H H 1 H H NC(═O)OPh CF₃ H Me Me H H 1H H NC(═O)OPh OCHF₂ H Me Me H H 1 H H NC(═O)NHMe Cl Me Me Me H H 1 H HNC(═O)NHMe CF₃ H Me Me H H 1 H H NC(═O)NHMe OCHF₂ H Me Me H H 1 H HNC(═O)N(Me)₂ Cl Me Me Me H H 1 H H NC(═O)N(Me)₂ CF₃ H Me Me H H 1 H HNC(═O)N(Me)₂ OCHF₂ H H H H H 1 H H NPh Cl Me Me H H H 1 H H NPh Cl Me MeH Me H 1 H H NPh Cl Me Me Me H H 1 Me H NPh Cl Me Me Me H H 1 Et H NPhCl Me Me Me H H 1 Pr-i H NPh Cl Me Me Me H H 1 Me Me NPh Cl Me Me Et H H1 H H NPh Cl Me Et Et H H 1 H H NPh Cl Me Me Pr-i H H 1 H H NPh Cl Me MePr H H 1 H H NPh Cl Me Me Pr-c H H 1 H H NPh Cl Me Me CH₂Pr-c H H 1 H HNPh Cl Me —(CH₂)₂— H H 1 H H NPh Cl Me —(CH₂)₃— H H 1 H H NPh Cl Me—(CH₂)₄— H H 1 H H NPh Cl Me —(CH₂)₅— H H 1 H H NPh Cl Me H —(CH₂)₃— H 1H H NPh Cl Me H —(CH₂)₄— H 1 H H NPh Cl Me H —(CH₂)₅— H 1 H H NPh Cl MeH —(CH₂)₆— H 1 H H NPh Cl Me Me Me H H 1 H H O H Me Me Me H H 1 H H O ClMe Me Me H H 1 H H S H Me Me Me H H 1 H H S Cl Me Me Me H H 0 H H NMe ClH Me Me H H 0 H H NMe Cl Me Me Me H H 0 H H NMe Cl Et Me Me H H 0 H HNMe Cl CF₃ Me Me H H 0 H H NMe CF₃ H Me Me H H 0 H H MAe CF₃ Me Me Me HH 0 H H NMe OCHF₂ H Me Me H H 0 H H NMe OCHF₂ Me Me Me H H 0 H H NMeC(═O)Me H Me Me H H 0 H H NMe C(═O)Me Me Me Me H H 0 H H NMe —(CH₂)₃— MeMe H H 0 H H NMe —(CH₂)₄— Me Me H H 0 H H NEt Cl Me Me Me H H 0 H H NEtCF₃ H Me Me H H 0 H H NEt CF₃ Me Me Me H H 0 H H NEt OCHF₂ H Me Me H H 0H H NEt OCHF₂ Me Me Me H H 0 H H NEt —(CH₂)₃— Me Me H H 0 H H NEt—(CH₂)₄— Me Me H H 0 H H NPr-i Cl Me Me Me H H 0 H H NPr-i CF₃ H Me Me HH 0 H H NPr-i CF₃ Me Me Me H H 0 H H NPr-i OCHF₂ H Me Me H H 0 H H NPr-iOCHF₂ Me Me Me H H 0 H H NPr-i —(CH₂)₃— Me Me H H 0 H H NPr-i —(CH₂)₄—Me Me H H 0 H H NPr Cl Me Me Me H H 0 H H NPr CF₃ H Me Me H H 0 H H NPrCF₃ Me Me Me H H 0 H H NPr OCHF₂ H Me Me H H 0 H H NPr OCHF₂ Me Me Me HH 0 H H NPr —(CH₂)₃— Me Me H H 0 H H NPr —(CH₂)₄— Me Me H H 0 H H NBu-tCl Me Me Me H H 0 H H NBu-t CF₃ H Me Me H H 0 H H NBu-t CF₃ Me Me Me H H0 H H NBu-t OCHF₂ H Me Me H H 0 H H NBu-t OCHF₂ Me Me Me H H 0 H H NBu-t—(CH₂)₃— Me Me H H 0 H H NBu-t —(CH₂)₄— Me Me H H 0 H H NCH₂Ph Cl Me MeMe H H 0 H H NCH₂Ph CF₃ H Me Me H H 0 H H NCH₂Ph OCHF₂ H Me Me H H 0 H HNCH₂OMe Cl Me Me Me H H 0 H H NCH₂OMe CF₃ H Me Me H H 0 H H NCH₂OMeOCHF₂ H Me Me H H 0 H H NCH₂C≡CH Cl Me Me Me H H 0 H H NCH₂C≡CH CF₃ H MeMe H H 0 H H NCH₂C≡CH OCHF₂ H Me Me H H 0 H H NCH₂CH═CH₂ Cl Me Me Me H H0 H H NCH₂CH═CH₂ CF₃ H Me Me H H 0 H H NCH₂CH═CH₂ OCHF₂ H Me Me H H 0 HH NCHF₂ Cl Me Me Me H H 0 H H NCHF₂ CF₃ H Me Me H H 0 H H NCHF₂ CF₃ MeMe Me H H 0 H H NCHF₂ OCHF₂ H Me Me H H 0 H H NCHF₂ OCHF₂ Me Me Me H H 0H H NCHF₂ C(═O)Me H Me Me H H 0 H H NCHF₂ C(═O)Me Me Me Me H H 0 H HNCHF₂ —(CH₂)₃— Me Me H H 0 H H NCHF₂ —(CH₂)₄— Me Me H H 0 H H NPh OMe MeMe Me H H 0 H H NPh OEt Me Me Me H H 0 H H NPh OCHF₂ Me Me Me H H 0 H HNPh OCH₂CF₃ Me Me Me H H 0 H H NPh CF₃ H Me Me H H 0 H H NPh OCH₂CH═CH₂Me Me Me H H 0 H H NPh OCH₂CH≡CH Me Me Me H H 0 H H NPh Cl Me Me Me H H0 H H N(2-Cl)Ph Cl Me Me Me H H 0 H H N(2-F)Ph Cl Me Me Me H H 0 H HN(2-OMe)Ph Cl Me Me Me H H 0 H H N(2-Me)Ph Cl Me Me Me H H 0 H HN(3-Cl)Ph Cl Me Me Me H H 0 H H N(3-F)Ph Cl Me Me Me H H 0 H HN(3-OMe)Ph Cl Me Me Me H H 0 H H N(3-Me)Ph Cl Me Me Me H H 0 H HN(4-Cl)Ph Cl Me Me Me H H 0 H H N(4-F)Ph Cl Me Me Me H H 0 H HN(4-OMe)Ph Cl Me Me Me H H 0 H H N(4-Me)Ph Cl Me Me Me H H 0 H HN(Thiophen-2-yl) Cl Me Me Me H H 0 H H N(Thiophen-2-yl) CF₃ H Me Me H H0 H H N(Thiophen-2-yl) OCHF₂ H Me Me H H 0 H H NC(═O)Me Cl Me Me Me H H0 H H NC(═O)Me CF₃ H Me Me H H 0 H H NC(═O)Me OCHF₂ H Me Me H H 0 H HNC(═O)CF₃ Cl Me Me Me H H 0 H H NC(═O)CF₃ CF₃ H Me Me H H 0 H HNC(═O)CF₃ OCHF₂ H Me Me H H 0 H H NC(═O)CH₂Ph Cl Me Me Me H H 0 H HNC(═O)CH₂Ph CF₃ H Me Me H H 0 H H NC(═O)CH₂Ph OCHF₂ H Me Me H H 0 H HNC(═O)Ph Cl Me Me Me H H 0 H H NC(═O)Ph CF₃ H Me Me H H 0 H H NC(═O)PhOCHF₂ H Me Me H H 0 H H NC(═O)OMe Cl Me Me Me H H 0 H H NC(═O)OMe CF₃ HMe Me H H 0 H H NC(═O)OMe OCHF₂ H Me Me H H 0 H H NC(═O)OCH₂Ph Cl Me MeMe H H 0 H H NC(═O)OCH₂Ph CF₃ H Me Me H H 0 H H NC(═O)OCH₂Ph OCHF₂ H MeMe H H 0 H H NC(═O)OPh Cl Me Me Me H H 0 H H NC(═O)OPh CF₃ H Me Me H H 0H H NC(═O)OPh OCHF₂ H Me Me H H 0 H H NC(═O)NHMe Cl Me Me Me H H 0 H HNC(═O)NHMe CF₃ H Me Me H H 0 H H NC(═O)NHMe OCHF₂ H Me Me H H 0 H HNC(═O)N(Me)₂ Cl Me Me Me H H 0 H H NC(═O)N(Me)₂ CF₃ H Me Me H H 0 H HNC(═O)N(Me)₂ OCHF₂ H H H H H 0 H H NPh Cl Me Me H H H 0 H H NPh Cl Me MeH Me H 0 H H NPh Cl Me Me Me H H 0 Me H NPh Cl Me Me Me H H 0 Et H NPhCl Me Me Me H H 0 Pr-i H NPh Cl Me Me Me H H 0 Me Me NPh Cl Me Me Et H H0 H H NPh Cl Me Et Et H H 0 H H NPh Cl Me Me Pr-i H H 0 H H NPh Cl Me MePr H H 0 H H NPh Cl Me Me Pr-c H H 0 H H NPh Cl Me Me CH₂Pr-c H H 0 H HNPh Cl Me —(CH₂)₂— H H 0 H H NPh Cl Me —(CH₂)₃— H H 0 H H NPh Cl Me—(CH₂)₄— H H 0 H H NPh Cl Me —(CH₂)₅— H H 0 H H NPh Cl Me H —(CH₂)₃— H 0H H NPh Cl Me H —(CH₂)₄— H 0 H H NPh Cl Me H —(CH₂)₅— H 0 H H NPh Cl MeH —(CH₂)₆— H 0 H H NPh Cl Me Me Me H H 0 H H O H Me Me Me H H 0 H H O ClMe Me Me H H 0 H H S H Me Me Me H H 0 H H S Cl Me Me Et H H 2 H H NH H H

TABLE 6

R¹ R² R³ R⁴ n R⁵ R⁶ Z⁵ R³⁵ R³⁶ Me Me H H 2 H H NMe H OMe Me Me H H 2 H HNMe H OEt Me Me H H 2 H H NMe H OCHF₂ Me Me H H 2 H H NMe H OCH₂CF₃ MeMe H H 2 H H NMe —(CH₂)₃— Me Me H H 2 H H NMe —(CH₂)₄— Me Me H H 2 H HNEt —(CH₂)₃— Me Me H H 2 H H NEt —(CH₂)₄— Me Me H H 2 H H NPr-i —(CH₂)₃—Me Me H H 2 H H NPr-i —(CH₂)₄— Me Me H H 2 H H NCHF₂ —(CH₂)₃— Me Me H H2 H H NCHF₂ —(CH₂)₄— Me Me H H 2 H H N(CH₂)₃O— H Me Me H H 2 H HN(CH₂)₄O— H Me Me H H 2 H H N(CH₂)₄— H Me Me H H 2 H H N(CH₂)₅— H Me MeH H 2 H H NPh H OMe Me Me H H 2 H H NPh H OEt Me Me H H 2 H H NPh HOCHF₂ Me Me H H 2 H H NPh H OCH₂CF₃ Me Me H H 2 H H O Me H Me Me H H 2 HH S Me H H H H H 2 H H NPh H OMe Me H H H 2 H H NPh H OEt Me H Me H 2 HH NPh H OMe Me Me H H 2 Me H NPh H OEt Me Me H H 2 Et H NPh H OMe Me MeH H 2 Pr-i H NPh H OEt Me Me H H 2 Me Me NPh H OMe Me Et H H 2 H H NPh HOEt Et Et H H 2 H H NPh H OMe Me Pr-i H H 2 H H NPh H OEt Me Pr H H 2 HH NPh H OMe Me Pr-c H H 2 H H NPh H OEt Me CH₂Pr-c H H 2 H H NPh H OMe—(CH₂)₂— H H 2 H H NPh H OEt —(CH₂)₃— H H 2 H H NPh H OMe —(CH₂)₄— H H 2H H NPh H OEt —(CH₂)₅— H H 2 H H NPh H OMe H —(CH₂)₃— H 2 H H NPh H OEtH —(CH₂)₄— H 2 H H NPh H OMe H —(CH₂)₅— H 2 H H NPh H OMe H —(CH₂)₆— H 2H H NPh H OEt Me Me H H 1 H H NMe H OMe Me Me H H 1 H H NMe H OEt Me MeH H 1 H H NMe H OCHF₂ Me Me H H 1 H H NMe H OCH₂CF₃ Me Me H H 1 H H NMe—(CH₂)₃— Me Me H H 1 H H NMe —(CH₂)₄— Me Me H H 1 H H NEt —(CH₂)₃— Me MeH H 1 H H NEt —(CH₂)₄— Me Me H H 1 H H NPr-i —(CH₂)₃— Me Me H H 1 H HNPr-i —(CH₂)₄— Me Me H H 1 H H NCHF₂ —(CH₂)₃— Me Me H H 1 H H NCHF₂—(CH₂)₄— Me Me H H 1 H H N(CH₂)₃O— H Me Me H H 1 H H N(CH₂)₄O— H Me Me HH 1 H H N(CH₂)₄— H Me Me H H 1 H H N(CH₂)₅— H Me Me H H 1 H H NPh H OMeMe Me H H 1 H H NPh H OEt Me Me H H 1 H H NPh H OCHF₂ Me Me H H 1 H HNPh H OCH₂CF₃ Me Me H H 1 H H O Me H Me Me H H 1 H H S Me H H H H H 1 HH NPh H OMe Me H H H 1 H H NPh H OEt Me H Me H 1 H H NPh H OMe Me Me H H1 Me H NPh H OEt Me Me H H 1 Et H NPh H OMe Me Me H H 1 Pr-i H NPh H OEtMe Me H H 1 Me Me NPh H OMe Me Et H H 1 H H NPh H OEt Et Et H H 1 H HNPh H OMe Me Pr-i H H 1 H H NPh H OEt Me Pr H H 1 H H NPh H OMe Me Pr-cH H 1 H H NPh H OEt Me CH₂Pr-c H H 1 H H NPh H OMe —(CH₂)₂— H H 1 H HNPh H OEt —(CH₂)₃— H H 1 H H NPh H OMe —(CH₂)₄— H H 1 H H NPh H OEt—(CH₂)₅— H H 1 H H NPh H OMe H —(CH₂)₃— H 1 H H NPh H OEt H —(CH₂)₄— H 1H H NPh H OMe H —(CH₂)₅— H 1 H H NPh H OMe H —(CH₂)₆— H 1 H H NPh H OEtMe Me H H 0 H H NMe H OMe Me Me H H 0 H H NMe H OEt Me Me H H 0 H H NMeH OCHF₂ Me Me H H 0 H H NMe H OCH₂CF₃ Me Me H H 0 H H NMe —(CH₂)₃— Me MeH H 0 H H NMe —(CH₂)₄— Me Me H H 0 H H NEt —(CH₂)₃— Me Me H H 0 H H NEt—(CH₂)₄— Me Me H H 0 H H NPr-i —(CH₂)₃— Me Me H H 0 H H NPr-i —(CH₂)₄—Me Me H H 0 H H NCHF₂ —(CH₂)₃— Me Me H H 0 H H NCHF₂ —(CH₂)₄— Me Me H H0 H H N(CH₂)₃O— H Me Me H H 0 H H N(CH₂)₄O— H Me Me H H 0 H H N(CH₂)₄— HMe Me H H 0 H H N(CH₂)₅— H Me Me H H 0 H H NPh H OMe Me Me H H 0 H H NPhH OEt Me Me H H 0 H H NPh H OCHF₂ Me Me H H 0 H H NPh H OCH₂CF₃ Me Me HH 0 H H O Me H Me Me H H 0 H H S Me H H H H H 0 H H NPh H OMe Me H H H 0H H NPh H OEt Me H Me H 0 H H NPh H OMe Me Me H H 0 Me H NPh H OEt Me MeH H 0 Et H NPh H OMe Me Me H H 0 Pr-i H NPh H OEt Me Me H H 0 Me Me NPhH OMe Me Et H H 0 H H NPh H OEt Et Et H H 0 H H NPh H OMe Me Pr-i H H 0H H NPh H OEt Me Pr H H 0 H H NPh H OMe Me Pr-c H H 0 H H NPh H OEt MeCH₂Pr-c H H 0 H H NPh H OMe —(CH₂)₂— H H 0 H H NPh H OEt —(CH₂)₃— H H 0H H NPh H OMe —(CH₂)₄— H H 0 H H NPh H OEt —(CH₂)₅— H H 0 H H NPh H OMeH —(CH₂)₃— H 0 H H NPh H OEt H —(CH₂)₄— H 0 H H NPh H OMe H —(CH₂)₅— H 0H H NPh H OMe H —(CH₂)₆— H 0 H H NPh H OEt Me Et H H 2 H H O H H Me Et HH 2 H H S H H Me Et H H 2 H H NH H H

TABLE 7

R¹ R² R³ R⁴ n R⁵ R⁶ R³⁷ R³⁸ R³⁹ R⁴⁰ Me Me H H 2 H H H H H H — Me Me H H2 H H H H H H N-oxide Me Me H H 2 H H Cl Ph H H — Me Me H H 2 H H OMe PhH H — Me Me H H 2 H H Cl Me H H — Me Me H H 2 H H OMe Me H H — Me Me H H2 H H H CF₃ H H — Me Me H H 2 H H H CF₃ H H N-oxide Me Me H H 2 H H ClCF₃ H H — Me Me H H 2 H H CN CF₃ H H — Me Me H H 2 H H OMe CF₃ H H — MeMe H H 2 H H OEt CF₃ H H — Me Me H H 2 H H Me Me H H N-oxide Me Me H H 2H H Ph Ph H H — Me Me H H 2 H H Cl (4-Cl)Ph H Me — Me Me H H 2 H H Cl(4-Cl)Ph H H — Me Me H H 2 H H OMe Cl H H — Me Me H H 2 H H Cl (CH₂)₃ H— Me Me H H 2 H H Me (CH₂)₃ H — Me Me H H 2 H H Cl (CH₂)₄ H — Me Me H H2 H H Me (CH₂)₄ H — Me Me H H 2 H H Cl H (CH₂)₃ — Me Me H H 2 H H Me H(CH₂)₃ — Me Me H H 2 H H Cl H (CH₂)₄ — Me Me H H 2 H H Me H (CH₂)₄ — H HH H 2 H H H CF₃ H H — Me H H H 2 H H H CF₃ H H — Me H Me H 2 H H H CF₃ HH — Me Me Me H 2 H H H CF₃ H H — Me Me H H 2 Me H H CF₃ H H — Me Me H H2 Et H H CF₃ H H — Me Me H H 2 Pr-i H H CF₃ H H — Me Me H H 2 Me Me HCF₃ H H — Me Et H H 2 H H H CF₃ H H — Et Et H H 2 H H H CF₃ H H — MePr-i H H 2 H H H CF₃ H H — Me Pr H H 2 H H H CF₃ H H — Me Pr-c H H 2 H HH CF₃ H H — Me CH₂Pr-c H H 2 H H H CF₃ H H — —(CH₂)₂— H H 2 H H H CF₃ HH — —(CH₂)₃— H H 2 H H H CF₃ H H — —(CH₂)₄— H H 2 H H H CF₃ H H ——(CH₂)₅— H H 2 H H H CF₃ H H — H —(CH₂)₃— H 2 H H H CF₃ H H — H —(CH₂)₄—H 2 H H H CF₃ H H — H —(CH₂)₅— H 2 H H H CF₃ H H — H —(CH₂)₆— H 2 H H HCF₃ H H — Me Me H H 1 H H H H H H — Me Me H H 1 H H H H H H N-oxide MeMe H H 1 H H Cl Ph H H — Me Me H H 1 H H OMe Ph H H — Me Me H H 1 H H ClMe H H — Me Me H H 1 H H OMe Me H H — Me Me H H 1 H H H CF₃ H H — Me MeH H 1 H H Cl CF₃ H H — Me Me H H 1 H H CN CF₃ H H — Me Me H H 1 H H OMeCF₃ H H — Me Me H H 1 H H OEt CF₃ H H — Me Me H H 1 H H Me Me H HN-oxide Me Me H H 1 H H Ph Ph H H — Me Me H H 1 H H Cl (4-Cl)Ph H Me —Me Me H H 1 H H Cl (4-Cl)Ph H H — Me Me H H 1 H H OMe Cl H H — Me Me H H1 H H Cl (CH₂)₃ H — Me Me H H 1 H H Me (CH₂)₃ H — Me Me H H 1 H H Cl(CH₂)₄ H — Me Me H H 1 H H Me (CH₂)₄ H — Me Me H H 1 H H Cl H (CH₂)₃ —Me Me H H 1 H H Me H (CH₂)₃ — Me Me H H 1 H H Cl H (CH₂)₄ — Me Me H H 1H H Me H (CH₂)₄ — H H H H 1 H H H CF₃ H H — Me H H H 1 H H H CF₃ H H —Me H Me H 1 H H H CF₃ H H — Me Me Me H 1 H H H CF₃ H H — Me Me H H 1 MeH H CF₃ H H — Me Me H H 1 Et H H CF₃ H H — Me Me H H 1 Pr-i H H CF₃ H H— Me Me H H 1 Me Me H CF₃ H H — Me Et H H 1 H H H CF₃ H H — Et Et H H 1H H H CF₃ H H — Me Pr-i H H 1 H H H CF₃ H H — Me Pr H H 1 H H H CF₃ H H— Me Pr-c H H 1 H H H CF₃ H H — Me CH₂Pr-c H H 1 H H H CF₃ H H ——(CH₂)₂— H H 1 H H H CF₃ H H — —(CH₂)₃— H H 1 H H H CF₃ H H — —(CH₂)₄— HH 1 H H H CF₃ H H — —(CH₂)₅— H H 1 H H H CF₃ H H — H —(CH₂)₃— H 1 H H HCF₃ H H — H —(CH₂)₄— H 1 H H H CF₃ H H — H —(CH₂)₅— H 1 H H H CF₃ H H —H —(CH₂)₆— H 1 H H H CF₃ H H — Me Me H H 0 H H H H H H — Me Me H H 0 H HH H H H N-oxide Me Me H H 0 H H Cl Ph H H — Me Me H H 0 H H OMe Ph H H —Me Me H H 0 H H Cl Me H H — Me Me H H 0 H H OMe Me H H — Me Me H H 0 H HH CF₃ H H — Me Me H H 0 H H Cl CF₃ H H — Me Me H H 0 H H CN CF₃ H H — MeMe H H 0 H H OMe CF₃ H H — Me Me H H 0 H H OEt CF₃ H H — Me Me H H 0 H HMe Me H H N-oxide Me Me H H 0 H H Ph Ph H H — Me Me H H 0 H H Cl(4-Cl)Ph H Me — Me Me H H 0 H H Cl (4-Cl)Ph H H — Me Me H H 0 H H OMe ClH H — Me Me H H 0 H H Cl (CH₂)₃ H — Me Me H H 0 H H Me (CH₂)₃ H — Me MeH H 0 H H Cl (CH₂)₄ H — Me Me H H 0 H H Me (CH₂)₄ H — Me Me H H 0 H H ClH (CH₂)₃ — Me Me H H 0 H H Me H (CH₂)₃ — Me Me H H 0 H H Cl H (CH₂)₄ —Me Me H H 0 H H Me H (CH₂)₄ — Me Me H H 0 H H (2-Chloropyridin-3- H H H— yl)methylthio H H H H 0 H H H CF₃ H H — Me H H H 0 H H H CF₃ H H — MeMe Me H 0 H H H CF₃ H H — Me H Me H 0 H H H CF₃ H H — Me Me H H 0 Me H HCF₃ H H — Me Me H H 0 Et H H CF₃ H H — Me Me H H 0 Pr-i H H CF₃ H H — MeMe H H 0 Me Me H CF₃ H H — Me Et H H 0 H H H CF₃ H H — Et Et H H 0 H H HCF₃ H H — Me Pr-i H H 0 H H H CF₃ H H — Me Pr H H 0 H H H CF₃ H H — MePr-c H H 0 H H H CF₃ H H — Me CH₂Pr-c H H 0 H H H CF₃ H H — —(CH₂)₂— H H0 H H H CF₃ H H — —(CH₂)₃— H H 0 H H H CF₃ H H — —(CH₂)₄— H H 0 H H HCF₃ H H — —(CH₂)₅— H H 0 H H H CF₃ H H — H —(CH₂)₃— H 0 H H H CF₃ H H —H —(CH₂)₄— H 0 H H H CF₃ H H — H —(CH₂)₅— H 0 H H H CF₃ H H — H —(CH₂)₆—H 0 H H H CF₃ H H — Me Et H H 2 H H H H H H —

TABLE 8

R¹ R² R³ R⁴ n R⁵ R⁶ R⁴¹ R⁴² R⁴³ Me Me H H 2 H H H Cl Cl Me Me H H 2 H HH OH Cl Me Me H H 2 H H H OMe Cl Me Me H H 2 H H H OEt Cl Me Me H H 2 HH H OPr-i Cl Me Me H H 2 H H H OPr Cl Me Me H H 2 H H H OBu-t Cl Me Me HH 2 H H H OCH₂Pr-c Cl Me Me H H 2 H H H OCH₂Bu-c Cl Me Me H H 2 H H HOCH₂Pen-c Cl Me Me H H 2 H H H OCH₂Hex-c Cl Me Me H H 2 H H H OPen-c ClMe Me H H 2 H H H OHex-c Cl Me Me H H 2 H H H OCH₂Ph Cl Me Me H H 2 H HH OPh Cl Me Me H H 2 H H H OCHF₂ Cl Me Me H H 2 H H H SH Cl Me Me H H 2H H H SMe Cl Me Me H H 2 H H H SO₂Me Cl Me Me H H 2 H H H SEt Cl Me Me HH 2 H H H SO₂Et Cl Me Me H H 2 H H H SPr-i Cl Me Me H H 2 H H H SO₂Pr-iCl Me Me H H 2 H H H SPh Cl Me Me H H 2 H H H SO₂Ph Cl Me Me H H 2 H H HSCHF₂ Cl Me Me H H 2 H H H SO₂CHF₂ Cl Me Me H H 2 H H H NH₂ Cl Me Me H H2 H H H NHMe Cl Me Me H H 2 H H H NMe2 Cl Me Me H H 2 H H H NHEt Cl MeMe H H 2 H H H NEt₂ Cl Me Me H H 2 H H H NHPh Cl Me Me H H 2 H H HN(Me)Ph Cl Me Me H H 2 H H H CN Cl Me Me H H 2 H H H F Me Me Me H H 2 HH H Cl Me Me Me H H 2 H H H OH Me Me Me H H 2 H H H OMe Me Me Me H H 2 HH H OEt Me Me Me H H 2 H H H OPr-i Me Me Me H H 2 H H H OPr Me Me Me H H2 H H H OBu-t Me Me Me H H 2 H H H OCH₂Pr-c Me Me Me H H 2 H H HOCH₂Bu-c Me Me Me H H 2 H H H OCH₂Pen-c Me Me Me H H 2 H H H OCH₂Hex-cMe Me Me H H 2 H H H OPen-c Me Me Me H H 2 H H H OHex-c Me Me Me H H 2 HH H OCH₂Ph Me Me Me H H 2 H H H OPh Me Me Me H H 2 H H H OCHF₂ Me Me MeH H 2 H H H SH Me Me Me H H 2 H H H SMe Me Me Me H H 2 H H H SO₂Me Me MeMe H H 2 H H H SEt Me Me Me H H 2 H H H SO₂Et Me Me Me H H 2 H H H SPr-iMe Me Me H H 2 H H H SO₂Pr-i Me Me Me H H 2 H H H SPh Me Me Me H H 2 H HH SO₂Ph Me Me Me H H 2 H H H SCHF₂ Me Me Me H H 2 H H H SO₂CHF₂ Me Me MeH H 2 H H H NH₂ Me Me Me H H 2 H H H NHMe Me Me Me H H 2 H H H NMe₂ MeMe Me H H 2 H H H NHEt Me Me Me H H 2 H H H NEt₂ Me Me Me H H 2 H H HNHPh Me Me Me H H 2 H H H N(Me)Ph Me Me Me H H 2 H H H CN Me Me Me H H 2H H H F Pr-i Me Me H H 2 H H H Cl Pr-i Me Me H H 2 H H H OH Pr-i Me Me HH 2 H H H OMe Pr-i Me Me H H 2 H H H OEt Pr-i Me Me H H 2 H H H OPr-iPr-i Me Me H H 2 H H H OPr Pr-i Me Me H H 2 H H H OBu-t Pr-i Me Me H H 2H H H OCH₂Pr-c Pr-i Me Me H H 2 H H H OCH₂Bu-c Pr-i Me Me H H 2 H H HOCH₂Pen-c Pr-i Me Me H H 2 H H H OCH₂Hex-c Pr-i Me Me H H 2 H H H OPen-cPr-i Me Me H H 2 H H H OHex-c Pr-i Me Me H H 2 H H H OCH₂Ph Pr-i Me Me HH 2 H H H OPh Pr-i Me Me H H 2 H H H OCHF₂ Pr-i Me Me H H 2 H H H SHPr-i Me Me H H 2 H H H SMe Pr-i Me Me H H 2 H H H SO₂Me Pr-i Me Me H H 2H H H SEt Pr-i Me Me H H 2 H H H SO₂Et Pr-i Me Me H H 2 H H H SPr-i Pr-iMe Me H H 2 H H H SO₂Pr-i Pr-i Me Me H H 2 H H H SPh Pr-i Me Me H H 2 HH H SO₂Ph Pr-i Me Me H H 2 H H H SCHF₂ Pr-i Me Me H H 2 H H H SO₂CHF₂Pr-i Me Me H H 2 H H H NH₂ Pr-i Me Me H H 2 H H H NHMe Pr-i Me Me H H 2H H H NMe₂ Pr-i Me Me H H 2 H H H NHEt Pr-i Me Me H H 2 H H H NEt₂ Pr-iMe Me H H 2 H H H NHPh Pr-i Me Me H H 2 H H H N(Me)Ph Pr-i Me Me H H 2 HH H CN Pr-i Me Me H H 2 H H H F Pr-c Me Me H H 2 H H H Cl Pr-c Me Me H H2 H H H OH Pr-c Me Me H H 2 H H H OMe Pr-c Me Me H H 2 H H H OEt Pr-c MeMe H H 2 H H H OPr-i Pr-c Me Me H H 2 H H H OPr Pr-c Me Me H H 2 H H HOBu-t Pr-c Me Me H H 2 H H H OCH₂Pr-c Pr-c Me Me H H 2 H H H OCH₂Bu-cPr-c Me Me H H 2 H H H OCH₂Pen-c Pr-c Me Me H H 2 H H H OCH₂Hex-c Pr-cMe Me H H 2 H H H OPen-c Pr-c Me Me H H 2 H H H OHex-c Pr-c Me Me H H 2H H H OCH₂Ph Pr-c Me Me H H 2 H H H OPh Pr-c Me Me H H 2 H H H OCHF₂Pr-c Me Me H H 2 H H H SH Pr-c Me Me H H 2 H H H SMe Pr-c Me Me H H 2 HH H SO₂Me Pr-c Me Me H H 2 H H H SEt Pr-c Me Me H H 2 H H H SO₂Et Pr-cMe Me H H 2 H H H SPr-i Pr-c Me Me H H 2 H H H SO₂Pr-i Pr-c Me Me H H 2H H H SPh Pr-c Me Me H H 2 H H H SO₂Ph Pr-c Me Me H H 2 H H H SCHF₂ Pr-cMe Me H H 2 H H H SO₂CHF₂ Pr-c Me Me H H 2 H H H NH₂ Pr-c Me Me H H 2 HH H NHMe Pr-c Me Me H H 2 H H H NMe₂ Pr-c Me Me H H 2 H H H NHEt Pr-c MeMe H H 2 H H H NEt₂ Pr-c Me Me H H 2 H H H NHPh Pr-c Me Me H H 2 H H HN(Me)Ph Pr-c Me Me H H 2 H H H CN Pr-c Me Me H H 2 H H H F CHF₂ Me Me HH 2 H H H Cl CHF₂ Me Me H H 2 H H H OH CHF₂ Me Me H H 2 H H H OMe CHF₂Me Me H H 2 H H H OEt CHF₂ Me Me H H 2 H H H OPr-i CHF₂ Me Me H H 2 H HH OPr CHF₂ Me Me H H 2 H H H OBu-t CHF₂ Me Me H H 2 H H H OCH₂Pr-c CHF₂Me Me H H 2 H H H OCH₂Bu-c CHF₂ Me Me H H 2 H H H OCH₂Pen-c CHF₂ Me Me HH 2 H H H OCH₂Hex-c CHF₂ Me Me H H 2 H H H OPen-c CHF₂ Me Me H H 2 H H HOHex-c CHF₂ Me Me H H 2 H H H OCH₂Ph CHF₂ Me Me H H 2 H H H OPh CHF₂ MeMe H H 2 H H H OCHF₂ CHF₂ Me Me H H 2 H H H SH CHF₂ Me Me H H 2 H H HSMe CHF₂ Me Me H H 2 H H H SO₂Me CHF₂ Me Me H H 2 H H H SEt CHF₂ Me Me HH 2 H H H SO₂Et CHF₂ Me Me H H 2 H H H SPr-i CHF₂ Me Me H H 2 H H HSO₂Pr-i CHF₂ Me Me H H 2 H H H SPh CHF₂ Me Me H H 2 H H H SO₂Ph CHF₂ MeMe H H 2 H H H SCHF₂ CHF₂ Me Me H H 2 H H H SO₂CHF₂ CHF₂ Me Me H H 2 H HH NH₂ CHF₂ Me Me H H 2 H H H NHMe CHF₂ Me Me H H 2 H H H NMe₂ CHF₂ Me MeH H 2 H H H NHEt CHF₂ Me Me H H 2 H H H NEt₂ CHF₂ Me Me H H 2 H H H NHPhCHF₂ Me Me H H 2 H H H N(Me)Ph CHF₂ Me Me H H 2 H H H CN CHF₂ Me Me H H2 H H H F CF₃ Me Me H H 2 H H H Cl CF₃ Me Me H H 2 H H H OH CF₃ Me Me HH 2 H H H OMe CF₃ Me Me H H 2 H H H OEt CF₃ Me Me H H 2 H H H OPr-i CF₃Me Me H H 2 H H H OPr CF₃ Me Me H H 2 H H H OBu-t CF₃ Me Me H H 2 H H HOCH₂Pr-c CF₃ Me Me H H 2 H H H OCH₂Bu-c CF₃ Me Me H H 2 H H H OCH₂Pen-cCF₃ Me Me H H 2 H H H OCH₂Hex-c CF₃ Me Me H H 2 H H H OPen-c CF₃ Me Me HH 2 H H H OHex-c CF₃ Me Me H H 2 H H H OCH₂Ph CF₃ Me Me H H 2 H H H OPhCF₃ Me Me H H 2 H H H OCHF₂ CF₃ Me Me H H 2 H H H SH CF₃ Me Me H H 2 H HH SMe CF₃ Me Me H H 2 H H H SO₂Me CF₃ Me Me H H 2 H H H SEt CF₃ Me Me HH 2 H H H SO₂Et CF₃ Me Me H H 2 H H H SPr-i CF₃ Me Me H H 2 H H HSO₂Pr-i CF₃ Me Me H H 2 H H H SPh CF₃ Me Me H H 2 H H H SO₂Ph CF₃ Me MeH H 2 H H H SCHF₂ CF₃ Me Me H H 2 H H H SO₂CHF₂ CF₃ Me Me H H 2 H H HNH₂ CF₃ Me Me H H 2 H H H NHMe CF₃ Me Me H H 2 H H H NMe₂ CF₃ Me Me H H2 H H H NHEt CF₃ Me Me H H 2 H H H NEt₂ CF₃ Me Me H H 2 H H H NHPh CF₃Me Me H H 2 H H H N(Me)Ph CF₃ Me Me H H 2 H H H CN CF₃ Me Me H H 2 H H HF OMe Me Me H H 2 H H H OH OMe Me Me H H 2 H H H OMe OMe Me Me H H 2 H HH OEt OMe Me Me H H 2 H H H OPr-i OMe Me Me H H 2 H H H OPr OMe Me Me HH 2 H H H OBu-t OMe Me Me H H 2 H H H OCH₂Pr-c OMe Me Me H H 2 H H HOCH₂Bu-c OMe Me Me H H 2 H H H OCH₂Pen-c OMe Me Me H H 2 H H H OCH₂Hex-cOMe Me Me H H 2 H H H OPen-c OMe Me Me H H 2 H H H OHex-c OMe Me Me H H2 H H H OCH₂Ph OMe Me Me H H 2 H H H OPh OMe Me Me H H 2 H H H OCHF₂ OMeMe Me H H 2 H H H SH OMe Me Me H H 2 H H H SMe OMe Me Me H H 2 H H HSO₂Me OMe Me Me H H 2 H H H SEt OMe Me Me H H 2 H H H SO₂Et OMe Me Me HH 2 H H H SPr-i OMe Me Me H H 2 H H H SO₂Pr-i OMe Me Me H H 2 H H H SPhOMe Me Me H H 2 H H H SO₂Ph OMe Me Me H H 2 H H H SCHF₂ OMe Me Me H H 2H H H SO₂CHF₂ OMe Me Me H H 2 H H H NH₂ OMe Me Me H H 2 H H H NHMe OMeMe Me H H 2 H H H NMe₂ OMe Me Me H H 2 H H H NHEt OMe Me Me H H 2 H H HNEt₂ OMe Me Me H H 2 H H H NHPh OMe Me Me H H 2 H H H N(Me)Ph OMe Me MeH H 2 H H H CN OMe Me Me H H 2 H H H F OPh Me Me H H 2 H H H OH OPh MeMe H H 2 H H H OMe OPh Me Me H H 2 H H H OEt OPh Me Me H H 2 H H H OPr-iOPh Me Me H H 2 H H H OPr OPh Me Me H H 2 H H H OBu-t OPh Me Me H H 2 HH H OCH₂Pr-c OPh Me Me H H 2 H H H OCH₂Bu-c OPh Me Me H H 2 H H HOCH₂Pen-c OPh Me Me H H 2 H H H OCH₂Hex-c OPh Me Me H H 2 H H H OPen-cOPh Me Me H H 2 H H H OHex-c OPh Me Me H H 2 H H H OCH₂Ph OPh Me Me H H2 H H H OPh OPh Me Me H H 2 H H H OCHF₂ OPh Me Me H H 2 H H H SH OPh MeMe H H 2 H H H SMe OPh Me Me H H 2 H H H SO₂Me OPh Me Me H H 2 H H H SEtOPh Me Me H H 2 H H H SO₂Et OPh Me Me H H 2 H H H SPr-i OPh Me Me H H 2H H H SO₂Pr-i OPh Me Me H H 2 H H H SPh OPh Me Me H H 2 H H H SO₂Ph OPhMe Me H H 2 H H H SCHF₂ OPh Me Me H H 2 H H H SO₂CHF₂ OPh Me Me H H 2 HH H NH₂ OPh Me Me H H 2 H H H NHMe OPh Me Me H H 2 H H H NMe₂ OPh Me MeH H 2 H H H NHEt OPh Me Me H H 2 H H H NEt₂ OPh Me Me H H 2 H H H NHPhOPh Me Me H H 2 H H H N(Me)Ph OPh Me Me H H 2 H H H CN OPh Me Me H H 2 HH H F OCHF₂ Me Me H H 2 H H H OH OCHF₂ Me Me H H 2 H H H OMe OCHF₂ Me MeH H 2 H H H OEt OCHF₂ Me Me H H 2 H H H OPr-i OCHF₂ Me Me H H 2 H H HOPr OCHF₂ Me Me H H 2 H H H OBu-t OCHF₂ Me Me H H 2 H H H OCH₂Pr-c OCHF₂Me Me H H 2 H H H OCH₂Bu-c OCHF₂ Me Me H H 2 H H H OCH₂Pen-c OCHF₂ Me MeH H 2 H H H OCH₂Hex-c OCHF₂ Me Me H H 2 H H H OPen-c OCHF₂ Me Me H H 2 HH H OHex-c OCHF₂ Me Me H H 2 H H H OCH₂Ph OCHF₂ Me Me H H 2 H H H OPhOCHF₂ Me Me H H 2 H H H OCHF₂ OCHF₂ Me Me H H 2 H H H SH OCHF₂ Me Me H H2 H H H SMe OCHF₂ Me Me H H 2 H H H SO₂Me OCHF₂ Me Me H H 2 H H H SEtOCHF₂ Me Me H H 2 H H H SO₂Et OCHF₂ Me Me H H 2 H H H SPr-i OCHF₂ Me MeH H 2 H H H SO₂Pr-i OCHF₂ Me Me H H 2 H H H SPh OCHF₂ Me Me H H 2 H H HSO₂Ph OCHF₂ Me Me H H 2 H H H SCHF₂ OCHF₂ Me Me H H 2 H H H SO₂CHF₂OCHF₂ Me Me H H 2 H H H NH₂ OCHF₂ Me Me H H 2 H H H NHMe OCHF₂ Me Me H H2 H H H NMe₂ OCHF₂ Me Me H H 2 H H H NHEt OCHF₂ Me Me H H 2 H H H NEt₂OCHF₂ Me Me H H 2 H H H NHPh OCHF₂ Me Me H H 2 H H H N(Me)Ph OCHF₂ Me MeH H 2 H H H CN OCHF₂ Me Me H H 2 H H Me F CF₃ Me Me H H 2 H H Me Cl CF₃Me Me H H 2 H H Me OH CF₃ Me Me H H 2 H H Me OMe CF₃ Me Me H H 2 H H MeOEt CF₃ Me Me H H 2 H H Me OPr-i CF₃ Me Me H H 2 H H Me OPr CF₃ Me Me HH 2 H H Me OBu-t CF₃ Me Me H H 2 H H Me OCH₂Pr-c CF₃ Me Me H H 2 H H MeOCH₂Bu-c CF₃ Me Me H H 2 H H Me OCH₂Pen-c CF₃ Me Me H H 2 H H MeOCH₂Hex-c CF₃ Me Me H H 2 H H Me OPen-c CF₃ Me Me H H 2 H H Me OHex-cCF₃ Me Me H H 2 H H Me OCH₂Ph CF₃ Me Me H H 2 H H Me OPh CF₃ Me Me H H 2H H Me OCHF₂ CF₃ Me Me H H 2 H H Me SH CF₃ Me Me H H 2 H H Me SMe CF₃ MeMe H H 2 H H Me SO₂Me CF₃ Me Me H H 2 H H Me SEt CF₃ Me Me H H 2 H H MeSO₂Et CF₃ Me Me H H 2 H H Me SPr-i CF₃ Me Me H H 2 H H Me SO₂Pr-i CF₃ MeMe H H 2 H H Me SPh CF₃ Me Me H H 2 H H Me SO₂Ph CF₃ Me Me H H 2 H H MeSCHF₂ CF₃ Me Me H H 2 H H Me SO₂CHF₂ CF₃ Me Me H H 2 H H Me NH₂ CF₃ MeMe H H 2 H H Me NHMe CF₃ Me Me H H 2 H H Me NMe₂ CF₃ Me Me H H 2 H H MeNHEt CF₃ Me Me H H 2 H H Me NEt₂ CF₃ Me Me H H 2 H H Me NHPh CF₃ Me Me HH 2 H H Me N(Me)Ph CF₃ Me Me H H 2 H H Me CN CF₃ Me Me H H 2 H H OMe FCF₃ Me Me H H 2 H H OMe Cl CF₃ Me Me H H 2 H H OMe OH CF₃ Me Me H H 2 HH OMe OMe CF₃ Me Me H H 2 H H OMe OEt CF₃ Me Me H H 2 H H OMe OPr-i CF₃Me Me H H 2 H H OMe OPr CF₃ Me Me H H 2 H H OMe OBu-t CF₃ Me Me H H 2 HH OMe OCH₂Pr-c CF₃ Me Me H H 2 H H OMe OCH₂Bu-c CF₃ Me Me H H 2 H H OMeOCH₂Pen-c CF₃ Me Me H H 2 H H OMe OCH₂Hex-c CF₃ Me Me H H 2 H H OMeOPen-c CF₃ Me Me H H 2 H H OMe OHex-c CF₃ Me Me H H 2 H H OMe OCH₂Ph CF₃Me Me H H 2 H H OMe OPh CF₃ Me Me H H 2 H H OMe OCHF₂ CF₃ Me Me H H 2 HH OMe SH CF₃ Me Me H H 2 H H OMe SMe CF₃ Me Me H H 2 H H OMe SO₂Me CF₃Me Me H H 2 H H OMe SEt CF₃ Me Me H H 2 H H OMe SO₂Et CF₃ Me Me H H 2 HH OMe SPr-i CF₃ Me Me H H 2 H H OMe SO₂Pr-i CF₃ Me Me H H 2 H H OMe SPhCF₃ Me Me H H 2 H H OMe SO₂Ph CF₃ Me Me H H 2 H H OMe SCHF₂ CF₃ Me Me HH 2 H H OMe SO₂CHF₂ CF₃ Me Me H H 2 H H OMe NH₂ CF₃ Me Me H H 2 H H OMeNHMe CF₃ Me Me H H 2 H H OMe NMe₂ CF₃ Me Me H H 2 H H OMe NHEt CF₃ Me MeH H 2 H H OMe NEt₂ CF₃ Me Me H H 2 H H OMe NHPh CF₃ Me Me H H 2 H H OMeN(Me)Ph CF₃ Me Me H H 2 H H OMe CN CF₃ Me Me H H 2 H H SMe F CF₃ Me Me HH 2 H H SMe Cl CF₃ Me Me H H 2 H H SMe OH CF₃ Me Me H H 2 H H SMe OMeCF₃ Me Me H H 2 H H SMe OEt CF₃ Me Me H H 2 H H SMe OPr-i CF₃ Me Me H H2 H H SMe OPr CF₃ Me Me H H 2 H H SMe OBu-t CF₃ Me Me H H 2 H H SMeOCH₂Pr-c CF₃ Me Me H H 2 H H SMe OCH₂Bu-c CF₃ Me Me H H 2 H H SMeOCH₂Pen-c CF₃ Me Me H H 2 H H SMe OCH₂Hex-c CF₃ Me Me H H 2 H H SMeOPen-c CF₃ Me Me H H 2 H H SMe OHex-c CF₃ Me Me H H 2 H H SMe OCH₂Ph CF₃Me Me H H 2 H H SMe OPh CF₃ Me Me H H 2 H H SMe OCHF₂ CF₃ Me Me H H 2 HH SMe SH CF₃ Me Me H H 2 H H SMe SMe CF₃ Me Me H H 2 H H SMe SO₂Me CF₃Me Me H H 2 H H SMe SEt CF₃ Me Me H H 2 H H SMe SO₂Et CF₃ Me Me H H 2 HH SMe SPr-i CF₃ Me Me H H 2 H H SMe SO₂Pr-i CF₃ Me Me H H 2 H H SMe SPhCF₃ Me Me H H 2 H H SMe SO₂Ph CF₃ Me Me H H 2 H H SMe SCHF₂ CF₃ Me Me HH 2 H H SMe SO₂CHF₂ CF₃ Me Me H H 2 H H SMe NH₂ CF₃ Me Me H H 2 H H SMeNHMe CF₃ Me Me H H 2 H H SMe NMe₂ CF₃ Me Me H H 2 H H SMe NHEt CF₃ Me MeH H 2 H H SMe NEt₂ CF₃ Me Me H H 2 H H SMe NHPh CF₃ Me Me H H 2 H H SMeN(Me)Ph CF₃ Me Me H H 2 H H SMe CN CF₃ Me Me H H 2 H H SO₂Me F CF₃ Me MeH H 2 H H SO₂Me Cl CF₃ Me Me H H 2 H H SO₂Me OH CF₃ Me Me H H 2 H HSO₂Me OMe CF₃ Me Me H H 2 H H SO₂Me OEt CF₃ Me Me H H 2 H H SO₂Me OPr-iCF₃ Me Me H H 2 H H SO₂Me OPr CF₃ Me Me H H 2 H H SO₂Me OBu-t CF₃ Me MeH H 2 H H SO₂Me OCH2Pr-c CF₃ Me Me H H 2 H H SO₂Me OCH₂Bu-c CF₃ Me Me HH 2 H H SO₂Me OCH₂Pen-c CF₃ Me Me H H 2 H H SO₂Me OCH₂Hex-c CF₃ Me Me HH 2 H H SO₂Me OPen-c CF₃ Me Me H H 2 H H SO₂Me OHex-c CF₃ Me Me H H 2 HH SO₂Me OCH₂Ph CF₃ Me Me H H 2 H H SO₂Me OPh CF₃ Me Me H H 2 H H SO₂MeOCHF₂ CF₃ Me Me H H 2 H H SO₂Me SH CF₃ Me Me H H 2 H H SO₂Me SMe CF₃ MeMe H H 2 H H SO₂Me SO₂Me CF₃ Me Me H H 2 H H SO₂Me SEt CF₃ Me Me H H 2 HH SO₂Me SO₂Et CF₃ Me Me H H 2 H H SO₂Me SPr-i CF₃ Me Me H H 2 H H SO₂MeSO₂Pr-i CF₃ Me Me H H 2 H H SO₂Me SPh CF₃ Me Me H H 2 H H SO₂Me SO₂PhCF₃ Me Me H H 2 H H SO₂Me SCHF₂ CF₃ Me Me H H 2 H H SO₂Me SO₂CHF₂ CF₃ MeMe H H 2 H H SO₂Me NH₂ CF₃ Me Me H H 2 H H SO₂Me NHMe CF₃ Me Me H H 2 HH SO₂Me NMe₂ CF₃ Me Me H H 2 H H SO₂Me NHEt CF₃ Me Me H H 2 H H SO₂MeNEt₂ CF₃ Me Me H H 2 H H SO₂Me NHPh CF₃ Me Me H H 2 H H SO₂Me N(Me)PhCF₃ Me Me H H 2 H H SO₂Me CN CF₃ Me Me H H 2 H H NH₂ F CF₃ Me Me H H 2 HH NH₂ Cl CF₃ Me Me H H 2 H H NH₂ OH CF₃ Me Me H H 2 H H NH₂ OMe CF₃ MeMe H H 2 H H NH₂ OEt CF₃ Me Me H H 2 H H NH₂ OPr-i CF₃ Me Me H H 2 H HNH₂ OPr CF₃ Me Me H H 2 H H NH₂ OBu-t CF₃ Me Me H H 2 H H NH₂ OCH₂Pr-cCF₃ Me Me H H 2 H H NH₂ OCH₂Bu-c CF₃ Me Me H H 2 H H NH₂ OCH₂Pen-c CF₃Me Me H H 2 H H NH₂ OCH₂Hex-c CF₃ Me Me H H 2 H H NH₂ OPen-c CF₃ Me Me HH 2 H H NH₂ OHex-c CF₃ Me Me H H 2 H H NH₂ OCH₂Ph CF₃ Me Me H H 2 H HNH₂ OPh CF₃ Me Me H H 2 H H NH₂ OCHF₂ CF₃ Me Me H H 2 H H NH₂ SH CF₃ MeMe H H 2 H H NH₂ SMe CF₃ Me Me H H 2 H H NH₂ SO₂Me CF₃ Me Me H H 2 H HNH₂ SEt CF₃ Me Me H H 2 H H NH₂ SO₂Et CF₃ Me Me H H 2 H H NH₂ SPr-i CF₃Me Me H H 2 H H NH₂ SO₂Pr-i CF₃ Me Me H H 2 H H NH₂ SPh CF₃ Me Me H H 2H H NH₂ SO₂Ph CF₃ Me Me H H 2 H H NH₂ SCHF₂ CF₃ Me Me H H 2 H H NH₂SO₂CHF₂ CF₃ Me Me H H 2 H H NH₂ NH₂ CF₃ Me Me H H 2 H H NH₂ NHMe CF₃ MeMe H H 2 H H NH₂ NMe₂ CF₃ Me Me H H 2 H H NH₂ NHEt CF₃ Me Me H H 2 H HNH₂ NEt₂ CF₃ Me Me H H 2 H H NH₂ NHPh CF₃ Me Me H H 2 H H NH₂ N(Me)PhCF₃ Me Me H H 2 H H NH₂ CN CF₃ H H H H 2 H H H OMe CF₃ H H H H 2 H H HOEt CF₃ Me H H H 2 H H H OMe CF₃ Me H H H 2 H H H OEt CF₃ Me H Me H 2 HH H OMe CF₃ Me H Me H 2 H H H OEt CF₃ Me Me H H 2 Me H H OMe CF₃ Me Me HH 2 Me H H OEt CF₃ Me Me H H 2 Et H H OMe CF₃ Me Me H H 2 Et H H OEt CF₃Me Me H H 2 Pr-i H H H CF₃ Me Me H H 2 Pr-i H H OMe CF₃ Me Me H H 2 Pr-iH H OEt CF₃ Me Me H H 2 Me Me H OMe CF₃ Me Me H H 2 Me Me H OEt CF₃ MeEt H H 2 H H H OMe CF₃ Me Et H H 2 H H H OEt CF₃ Et Et H H 2 H H H OMeCF₃ Et Et H H 2 H H H OEt CF₃ Me Pr-i H H 2 H H H OMe CF₃ Me Pr-i H H 2H H H OEt CF₃ Me Pr H H 2 H H H OMe CF₃ Me Pr H H 2 H H H OEt CF₃ MePr-c H H 2 H H H OMe CF₃ Me Pr-c H H 2 H H H OEt CF₃ Me CH₂Pr-c H H 2 HH H OMe CF₃ Me CH₂Pr-c H H 2 H H H OEt CF₃ —(CH₂)₂— H H 2 H H H OMe CF₃—(CH₂)₂— H H 2 H H H OEt CF₃ —(CH₂)₃— H H 2 H H H OMe CF₃ —(CH₂)₃— H H 2H H H OEt CF₃ —(CH₂)₄— H H 2 H H H OMe CF₃ —(CH₂)₄— H H 2 H H H OEt CF₃—(CH₂)₅— H H 2 H H H OMe CF₃ —(CH₂)₅— H H 2 H H H OEt CF₃ H —(CH₂)₃— H 2H H H OMe CF₃ H —(CH₂)₃— H 2 H H H OEt CF₃ H —(CH₂)₄— H 2 H H H OMe CF₃H —(CH₂)₄— H 2 H H H OEt CF₃ H —(CH₂)₅— H 2 H H H OMe CF₃ H —(CH₂)₅— H 2H H H OEt CF₃ H —(CH₂)₆— H 2 H H H OMe CF₃ H —(CH₂)₆— H 2 H H H OEt CF₃Me Me H H 1 H H H Cl Cl Me Me H H 1 H H H OH Cl Me Me H H 1 H H H OMe ClMe Me H H 1 H H H OEt Cl Me Me H H 1 H H H OPr-i Cl Me Me H H 1 H H HOPr Cl Me Me H H 1 H H H OBu-t Cl Me Me H H 1 H H H OCH₂Pr-c Cl Me Me HH 1 H H H OCH₂Bu-c Cl Me Me H H 1 H H H OCH₂Pen-c Cl Me Me H H 1 H H HOCH₂Hex-c Cl Me Me H H 1 H H H OPen-c Cl Me Me H H 1 H H H OHex-c Cl MeMe H H 1 H H H OCH₂Ph Cl Me Me H H 1 H H H OPh Cl Me Me H H 1 H H HOCHF₂ Cl Me Me H H 1 H H H SH Cl Me Me H H 1 H H H SMe Cl Me Me H H 1 HH H SO₂Me Cl Me Me H H 1 H H H SEt Cl Me Me H H 1 H H H SO₂Et Cl Me Me HH 1 H H H SPr-i Cl Me Me H H 1 H H H SO₂Pr-i Cl Me Me H H 1 H H H SPh ClMe Me H H 1 H H H SO₂Ph Cl Me Me H H 1 H H H SCHF₂ Cl Me Me H H 1 H H HSO₂CHF₂ Cl Me Me H H 1 H H H NH₂ Cl Me Me H H 1 H H H NHMe Cl Me Me H H1 H H H NMe₂ Cl Me Me H H 1 H H H NHEt Cl Me Me H H 1 H H H NEt₂ Cl MeMe H H 1 H H H NHPh Cl Me Me H H 1 H H H N(Me)Ph Cl Me Me H H 1 H H H CNCl Me Me H H 1 H H H F Me Me Me H H 1 H H H Cl Me Me Me H H 1 H H H OHMe Me Me H H 1 H H H OMe Me Me Me H H 1 H H H OEt Me Me Me H H 1 H H HOPr-i Me Me Me H H 1 H H H OPr Me Me Me H H 1 H H H OBu-t Me Me Me H H 1H H H OCH₂Pr-c Me Me Me H H 1 H H H OCH₂Bu-c Me Me Me H H 1 H H HOCH₂Pen-c Me Me Me H H 1 H H H OCH₂Hex-c Me Me Me H H 1 H H H OPen-c MeMe Me H H 1 H H H OHex-c Me Me Me H H 1 H H H OCH₂Ph Me Me Me H H 1 H HH OPh Me Me Me H H 1 H H H OCHF₂ Me Me Me H H 1 H H H SH Me Me Me H H 1H H H SMe Me Me Me H H 1 H H H SO₂Me Me Me Me H H 1 H H H SEt Me Me Me HH 1 H H H SO₂Et Me Me Me H H 1 H H H SPr-i Me Me Me H H 1 H H H SO₂Pr-iMe Me Me H H 1 H H H SPh Me Me Me H H 1 H H H SO₂Ph Me Me Me H H 1 H H HSCHF₂ Me Me Me H H 1 H H H SO₂CHF₂ Me Me Me H H 1 H H H NH₂ Me Me Me H H1 H H H NHMe Me Me Me H H 1 H H H NMe₂ Me Me Me H H 1 H H H NHEt Me MeMe H H 1 H H H NEt₂ Me Me Me H H 1 H H H NHPh Me Me Me H H 1 H H HN(Me)Ph Me Me Me H H 1 H H H CN Me Me Me H H 1 H H H F Pr-i Me Me H H 1H H H Cl Pr-i Me Me H H 1 H H H OH Pr-i Me Me H H 1 H H H OMe Pr-i Me MeH H 1 H H H OEt Pr-i Me Me H H 1 H H H OPr-i Pr-i Me Me H H 1 H H H OPrPr-i Me Me H H 1 H H H OBu-t Pr-i Me Me H H 1 H H H OCH₂Pr-c Pr-i Me MeH H 1 H H H OCH₂Bu-c Pr-i Me Me H H 1 H H H OCH₂Pen-c Pr-i Me Me H H 1 HH H OCH₂Hex-c Pr-i Me Me H H 1 H H H OPen-c Pr-i Me Me H H 1 H H HOHex-c Pr-i Me Me H H 1 H H H OCH₂Ph Pr-i Me Me H H 1 H H H OPh Pr-i MeMe H H 1 H H H OCHF₂ Pr-i Me Me H H 1 H H H SH Pr-i Me Me H H 1 H H HSMe Pr-i Me Me H H 1 H H H SO₂Me Pr-i Me Me H H 1 H H H SEt Pr-i Me Me HH 1 H H H SO₂Et Pr-i Me Me H H 1 H H H SPr-i Pr-i Me Me H H 1 H H HSO₂Pr-i Pr-i Me Me H H 1 H H H SPh Pr-i Me Me H H 1 H H H SO₂Ph Pr-i MeMe H H 1 H H H SCHF₂ Pr-i Me Me H H 1 H H H SO₂CHF₂ Pr-i Me Me H H 1 H HH NH₂ Pr-i Me Me H H 1 H H H NHMe Pr-i Me Me H H 1 H H H NMe₂ Pr-i Me MeH H 1 H H H NHEt Pr-i Me Me H H 1 H H H NEt₂ Pr-i Me Me H H 1 H H H NHPhPr-i Me Me H H 1 H H H N(Me)Ph Pr-i Me Me H H 1 H H H CN Pr-i Me Me H H1 H H H F Pr-c Me Me H H 1 H H H Cl Pr-c Me Me H H 1 H H H OH Pr-c Me MeH H 1 H H H OMe Pr-c Me Me H H 1 H H H OEt Pr-c Me Me H H 1 H H H OPr-iPr-c Me Me H H 1 H H H OPr Pr-c Me Me H H 1 H H H OBu-t Pr-c Me Me H H 1H H H OCH₂Pr-c Pr-c Me Me H H 1 H H H OCH₂Bu-c Pr-c Me Me H H 1 H H HOCH₂Pen-c Pr-c Me Me H H 1 H H H OCH₂Hex-c Pr-c Me Me H H 1 H H H OPen-cPr-c Me Me H H 1 H H H OHex-c Pr-c Me Me H H 1 H H H OCH₂Ph Pr-c Me Me HH 1 H H H OPh Pr-c Me Me H H 1 H H H OCHF₂ Pr-c Me Me H H 1 H H H SHPr-c Me Me H H 1 H H H SMe Pr-c Me Me H H 1 H H H SO₂Me Pr-c Me Me H H 1H H H SEt Pr-c Me Me H H 1 H H H SO₂Et Pr-c Me Me H H 1 H H H SPr-i Pr-cMe Me H H 1 H H H SO₂Pr-i Pr-c Me Me H H 1 H H H SPh Pr-c Me Me H H 1 HH H SO₂Ph Pr-c Me Me H H 1 H H H SCHF₂ Pr-c Me Me H H 1 H H H SO₂CHF₂Pr-c Me Me H H 1 H H H NH₂ Pr-c Me Me H H 1 H H H NHMe Pr-c Me Me H H 1H H H NMe₂ Pr-c Me Me H H 1 H H H NHEt Pr-c Me Me H H 1 H H H NEt₂ Pr-cMe Me H H 1 H H H NHPh Pr-c Me Me H H 1 H H H N(Me)Ph Pr-c Me Me H H 1 HH H CN Pr-c Me Me H H 1 H H H F CHF₂ Me Me H H 1 H H H Cl CHF₂ Me Me H H1 H H H OH CHF₂ Me Me H H 1 H H H OMe CHF₂ Me Me H H 1 H H H OEt CHF₂ MeMe H H 1 H H H OPr-i CHF₂ Me Me H H 1 H H H OPr CHF₂ Me Me H H 1 H H HOBu-t CHF₂ Me Me H H 1 H H H OCH₂Pr-c CHF₂ Me Me H H 1 H H H OCH₂Bu-cCHF₂ Me Me H H 1 H H H OCH₂Pen-c CHF₂ Me Me H H 1 H H H OCH₂Hex-c CHF₂Me Me H H 1 H H H OPen-c CHF₂ Me Me H H 1 H H H OHex-c CHF₂ Me Me H H 1H H H OCH₂Ph CHF₂ Me Me H H 1 H H H OPh CHF₂ Me Me H H 1 H H H OCHF₂CHF₂ Me Me H H 1 H H H SH CHF₂ Me Me H H 1 H H H SMe CHF₂ Me Me H H 1 HH H SO₂Me CHF₂ Me Me H H 1 H H H SEt CHF₂ Me Me H H 1 H H H SO₂Et CHF₂Me Me H H 1 H H H SPr-i CHF₂ Me Me H H 1 H H H SO₂Pr-i CHF₂ Me Me H H 1H H H SPh CHF₂ Me Me H H 1 H H H SO₂Ph CHF₂ Me Me H H 1 H H H SCHF₂ CHF₂Me Me H H 1 H H H SO₂CHF₂ CHF₂ Me Me H H 1 H H H NH₂ CHF₂ Me Me H H 1 HH H NHMe CHF₂ Me Me H H 1 H H H NMe₂ CHF₂ Me Me H H 1 H H H NHEt CHF₂ MeMe H H 1 H H H NEt₂ CHF₂ Me Me H H 1 H H H NHPh CHF₂ Me Me H H 1 H H HN(Me)Ph CHF₂ Me Me H H 1 H H H CN CHF₂ Me Me H H 1 H H H F CF₃ Me Me H H1 H H H Cl CF₃ Me Me H H 1 H H H OH CF₃ Me Me H H 1 H H H OMe CF₃ Me MeH H 1 H H H OEt CF₃ Me Me H H 1 H H H OPr-i CF₃ Me Me H H 1 H H H OPrCF₃ Me Me H H 1 H H H OBu-t CF₃ Me Me H H 1 H H H OCH₂Pr-c CF₃ Me Me H H1 H H H OCH₂Bu-c CF₃ Me Me H H 1 H H H OCH₂Pen-c CF₃ Me Me H H 1 H H HOCH₂Hex-c CF₃ Me Me H H 1 H H H OPen-c CF₃ Me Me H H 1 H H H OHex-c CF₃Me Me H H 1 H H H OCH₂Ph CF₃ Me Me H H 1 H H H OPh CF₃ Me Me H H 1 H H HOCHF₂ CF₃ Me Me H H 1 H H H SH CF₃ Me Me H H 1 H H H SMe CF₃ Me Me H H 1H H H SO₂Me CF₃ Me Me H H 1 H H H SEt CF₃ Me Me H H 1 H H H SO₂Et CF₃ MeMe H H 1 H H H SPr-i CF₃ Me Me H H 1 H H H SO₂Pr-i CF₃ Me Me H H 1 H H HSPh CF₃ Me Me H H 1 H H H SO₂Ph CF₃ Me Me H H 1 H H H SCHF₂ CF₃ Me Me HH 1 H H H SO₂CHF₂ CF₃ Me Me H H 1 H H H NH₂ CF₃ Me Me H H 1 H H H NHMeCF₃ Me Me H H 1 H H H NMe₂ CF₃ Me Me H H 1 H H H NHEt CF₃ Me Me H H 1 HH H NEt₂ CF₃ Me Me H H 1 H H H NHPh CF₃ Me Me H H 1 H H H N(Me)Ph CF₃ MeMe H H 1 H H H CN CF₃ Me Me H H 1 H H H F OMe Me Me H H 1 H H H OH OMeMe Me H H 1 H H H OMe OMe Me Me H H 1 H H H OEt OMe Me Me H H 1 H H HOPr-i OMe Me Me H H 1 H H H OPr OMe Me Me H H 1 H H H OBu-t OMe Me Me HH 1 H H H OCH₂Pr-c OMe Me Me H H 1 H H H OCH₂Bu-c OMe Me Me H H 1 H H HOCH₂Pen-c OMe Me Me H H 1 H H H OCH₂Hex-c OMe Me Me H H 1 H H H OPen-cOMe Me Me H H 1 H H H OHex-c OMe Me Me H H 1 H H H OCH₂Ph OMe Me Me H H1 H H H OPh OMe Me Me H H 1 H H H OCHF₂ OMe Me Me H H 1 H H H SH OMe MeMe H H 1 H H H SMe OMe Me Me H H 1 H H H SO₂Me OMe Me Me H H 1 H H H SEtOMe Me Me H H 1 H H H SO₂Et OMe Me Me H H 1 H H H SPr-i OMe Me Me H H 1H H H SO₂Pr-i OMe Me Me H H 1 H H H SPh OMe Me Me H H 1 H H H SO₂Ph OMeMe Me H H 1 H H H SCHF₂ OMe Me Me H H 1 H H H SO₂CHF₂ OMe Me Me H H 1 HH H NH₂ OMe Me Me H H 1 H H H NHMe OMe Me Me H H 1 H H H NMe₂ OMe Me MeH H 1 H H H NHEt OMe Me Me H H 1 H H H NEt₂ OMe Me Me H H 1 H H H NHPhOMe Me Me H H 1 H H H N(Me)Ph OMe Me Me H H 1 H H H CN OMe Me Me H H 1 HH H F OPh Me Me H H 1 H H H OH OPh Me Me H H 1 H H H OMe OPh Me Me H H 1H H H OEt OPh Me Me H H 1 H H H OPr-i OPh Me Me H H 1 H H H OPr OPh MeMe H H 1 H H H OBu-t OPh Me Me H H 1 H H H OCH₂Pr-c OPh Me Me H H 1 H HH OCH₂Bu-c OPh Me Me H H 1 H H H OCH₂Pen-c OPh Me Me H H 1 H H HOCH₂Hex-c OPh Me Me H H 1 H H H OPen-c OPh Me Me H H 1 H H H OHex-c OPhMe Me H H 1 H H H OCH₂Ph OPh Me Me H H 1 H H H OPh OPh Me Me H H 1 H H HOCHF₂ OPh Me Me H H 1 H H H SH OPh Me Me H H 1 H H H SMe OPh Me Me H H 1H H H SO₂Me OPh Me Me H H 1 H H H SEt OPh Me Me H H 1 H H H SO₂Et OPh MeMe H H 1 H H H SPr-i OPh Me Me H H 1 H H H SO₂Pr-i OPh Me Me H H 1 H H HSPh OPh Me Me H H 1 H H H SO₂Ph OPh Me Me H H 1 H H H SCHF₂ OPh Me Me HH 1 H H H SO₂CHF₂ OPh Me Me H H 1 H H H NH₂ OPh Me Me H H 1 H H H NHMeOPh Me Me H H 1 H H H NMe₂ OPh Me Me H H 1 H H H NHEt OPh Me Me H H 1 HH H NEt₂ OPh Me Me H H 1 H H H NHPh OPh Me Me H H 1 H H H N(Me)Ph OPh MeMe H H 1 H H H CN OPh Me Me H H 1 H H H F OCHF₂ Me Me H H 1 H H H OHOCHF₂ Me Me H H 1 H H H OMe OCHF₂ Me Me H H 1 H H H OEt OCHF₂ Me Me H H1 H H H OPr-i OCHF₂ Me Me H H 1 H H H OPr OCHF₂ Me Me H H 1 H H H OBu-tOCHF₂ Me Me H H 1 H H H OCH₂Pr-c OCHF₂ Me Me H H 1 H H H OCH₂Bu-c OCHF₂Me Me H H 1 H H H OCH₂Pen-c OCHF₂ Me Me H H 1 H H H OCH₂Hex-c OCHF₂ MeMe H H 1 H H H OPen-c OCHF₂ Me Me H H 1 H H H OHex-c OCHF₂ Me Me H H 1 HH H OCH₂Ph OCHF₂ Me Me H H 1 H H H OPh OCHF₂ Me Me H H 1 H H H OCHF₂OCHF₂ Me Me H H 1 H H H SH OCHF2 Me Me H H 1 H H H SMe OCHF₂ Me Me H H 1H H H SO₂Me OCHF2 Me Me H H 1 H H H SEt OCHF₂ Me Me H H 1 H H H SO₂EtOCHF₂ Me Me H H 1 H H H SPr-i OCHF₂ Me Me H H 1 H H H SO₂Pr-i OCHF₂ MeMe H H 1 H H H SPh OCHF₂ Me Me H H 1 H H H SO₂Ph OCHF₂ Me Me H H 1 H H HSCHF₂ OCHF₂ Me Me H H 1 H H H SO₂CHF₂ OCHF₂ Me Me H H 1 H H H NH₂ OCHF₂Me Me H H 1 H H H NHMe OCHF₂ Me Me H H 1 H H H NMe₂ OCHF₂ Me Me H H 1 HH H NHEt OCHF₂ Me Me H H 1 H H H NEt₂ OCHF₂ Me Me H H 1 H H H NHPh OCHF₂Me Me H H 1 H H H N(Me)Ph OCHF₂ Me Me H H 1 H H H CN OCHF₂ Me Me H H 1 HH Me F CF₃ Me Me H H 1 H H Me Cl CF₃ Me Me H H 1 H H Me OH CF₃ Me Me H H1 H H Me OMe CF₃ Me Me H H 1 H H Me OEt CF₃ Me Me H H 1 H H Me OPr-i CF₃Me Me H H 1 H H Me OPr CF₃ Me Me H H 1 H H Me OBu-t CF₃ Me Me H H 1 H HMe OCH₂Pr-c CF₃ Me Me H H 1 H H Me OCH₂Bu-c CF₃ Me Me H H 1 H H MeOCH₂Pen-c CF₃ Me Me H H 1 H H Me OCH₂Hex-c CF₃ Me Me H H 1 H H Me OPen-cCF₃ Me Me H H 1 H H Me OHex-c CF₃ Me Me H H 1 H H Me OCH₂Ph CF₃ Me Me HH 1 H H Me OPh CF₃ Me Me H H 1 H H Me OCHF₂ CF₃ Me Me H H 1 H H Me SHCF₃ Me Me H H 1 H H Me SMe CF₃ Me Me H H 1 H H Me SO₂Me CF₃ Me Me H H 1H H Me SEt CF₃ Me Me H H 1 H H Me SO₂Et CF₃ Me Me H H 1 H H Me SPr-i CF₃Me Me H H 1 H H Me SO₂Pr-i CF₃ Me Me H H 1 H H Me SPh CF₃ Me Me H H 1 HH Me SO₂Ph CF₃ Me Me H H 1 H H Me SCHF₂ CF₃ Me Me H H 1 H H Me SO₂CHF₂CF₃ Me Me H H 1 H H Me NH₂ CF₃ Me Me H H 1 H H Me NHMe CF₃ Me Me H H 1 HH Me NMe₂ CF₃ Me Me H H 1 H H Me NHEt CF₃ Me Me H H 1 H H Me NEt₂ CF₃ MeMe H H 1 H H Me NHPh CF₃ Me Me H H 1 H H Me N(Me)Ph CF₃ Me Me H H 1 H HMe CN CF₃ Me Me H H 1 H H OMe F CF₃ Me Me H H 1 H H OMe Cl CF₃ Me Me H H1 H H OMe OH CF₃ Me Me H H 1 H H OMe OMe CF₃ Me Me H H 1 H H OMe OEt CF₃Me Me H H 1 H H OMe OPr-i CF₃ Me Me H H 1 H H OMe OPr CF₃ Me Me H H 1 HH OMe OBu-t CF₃ Me Me H H 1 H H OMe OCH₂Pr-c CF₃ Me Me H H 1 H H OMeOCH₂Bu-c CF₃ Me Me H H 1 H H OMe OCH₂Pen-c CF₃ Me Me H H 1 H H OMeOCH₂Hex-c CF₃ Me Me H H 1 H H OMe OPen-c CF₃ Me Me H H 1 H H OMe OHex-cCF₃ Me Me H H 1 H H OMe OCH₂Ph CF₃ Me Me H H 1 H H OMe OPh CF₃ Me Me H H1 H H OMe OCHF₂ CF₃ Me Me H H 1 H H OMe SH CF₃ Me Me H H 1 H H OMe SMeCF₃ Me Me H H 1 H H OMe SO₂Me CF₃ Me Me H H 1 H H OMe SEt CF₃ Me Me H H1 H H OMe SO₂Et CF₃ Me Me H H 1 H H OMe SPr-i CF₃ Me Me H H 1 H H OMeSO₂Pr-i CF₃ Me Me H H 1 H H OMe SPh CF₃ Me Me H H 1 H H OMe SO₂Ph CF₃ MeMe H H 1 H H OMe SCHF₂ CF₃ Me Me H H 1 H H OMe SO₂CHF₂ CF₃ Me Me H H 1 HH OMe NH₂ CF₃ Me Me H H 1 H H OMe NHMe CF₃ Me Me H H 1 H H OMe NMe₂ CF₃Me Me H H 1 H H OMe NHEt CF₃ Me Me H H 1 H H OMe NEt₂ CF₃ Me Me H H 1 HH OMe NHPh CF₃ Me Me H H 1 H H OMe N(Me)Ph CF₃ Me Me H H 1 H H OMe CNCF₃ Me Me H H 1 H H SMe F CF₃ Me Me H H 1 H H SMe Cl CF₃ Me Me H H 1 H HSMe OH CF₃ Me Me H H 1 H H SMe OMe CF₃ Me Me H H 1 H H SMe OEt CF₃ Me MeH H 1 H H SMe OPr-i CF₃ Me Me H H 1 H H SMe OPr CF₃ Me Me H H 1 H H SMeOBu-t CF₃ Me Me H H 1 H H SMe OCH₂Pr-c CF₃ Me Me H H 1 H H SMe OCH₂Bu-cCF₃ Me Me H H 1 H H SMe OCH₂Pen-c CF₃ Me Me H H 1 H H SMe OCH₂Hex-c CF₃Me Me H H 1 H H SMe OPen-c CF₃ Me Me H H 1 H H SMe OHex-c CF₃ Me Me H H1 H H SMe OCH₂Ph CF₃ Me Me H H 1 H H SMe OPh CF₃ Me Me H H 1 H H SMeOCHF₂ CF₃ Me Me H H 1 H H SMe SH CF₃ Me Me H H 1 H H SMe SMe CF₃ Me Me HH 1 H H SMe SO₂Me CF₃ Me Me H H 1 H H SMe SEt CF₃ Me Me H H 1 H H SMeSO₂Et CF₃ Me Me H H 1 H H SMe SPr-i CF₃ Me Me H H 1 H H SMe SO₂Pr-i CF₃Me Me H H 1 H H SMe SPh CF₃ Me Me H H 1 H H SMe SO₂Ph CF₃ Me Me H H 1 HH SMe SCHF₂ CF₃ Me Me H H 1 H H SMe SO₂CHF₂ CF₃ Me Me H H 1 H H SMe NH₂CF₃ Me Me H H 1 H H SMe NHMe CF₃ Me Me H H 1 H H SMe NMe₂ CF₃ Me Me H H1 H H SMe NHEt CF₃ Me Me H H 1 H H SMe NEt₂ CF₃ Me Me H H 1 H H SMe NHPhCF₃ Me Me H H 1 H H SMe N(Me)Ph CF₃ Me Me H H 1 H H SMe CN CF₃ Me Me H H1 H H SO₂Me F CF₃ Me Me H H 1 H H SO₂Me Cl CF₃ Me Me H H 1 H H SO₂Me OHCF₃ Me Me H H 1 H H SO₂Me OMe CF₃ Me Me H H 1 H H SO₂Me OEt CF₃ Me Me HH 1 H H SO₂Me OPr-i CF₃ Me Me H H 1 H H SO₂Me OPr CF₃ Me Me H H 1 H HSO₂Me OBu-t CF₃ Me Me H H 1 H H SO₂Me OCH₂Pr-c CF₃ Me Me H H 1 H H SO₂MeOCH₂Bu-c CF₃ Me Me H H 1 H H SO₂Me OCH₂Pen-c CF₃ Me Me H H 1 H H SO₂MeOCH₂Hex-c CF₃ Me Me H H 1 H H SO₂Me OPen-c CF₃ Me Me H H 1 H H SO₂MeOHex-c CF₃ Me Me H H 1 H H SO₂Me OCH₂Ph CF₃ Me Me H H 1 H H SO₂Me OPhCF₃ Me Me H H 1 H H SO₂Me OCHF₂ CF₃ Me Me H H 1 H H SO₂Me SH CF₃ Me Me HH 1 H H SO₂Me SMe CF₃ Me Me H H 1 H H SO₂Me SO₂Me CF₃ Me Me H H 1 H HSO₂Me SEt CF₃ Me Me H H 1 H H SO₂Me SO₂Et CF₃ Me Me H H 1 H H SO₂MeSPr-i CF₃ Me Me H H 1 H H SO₂Me SO₂Pr-i CF₃ Me Me H H 1 H H SO₂Me SPhCF₃ Me Me H H 1 H H SO₂Me SO₂Ph CF₃ Me Me H H 1 H H SO₂Me SCHF₂ CF₃ MeMe H H 1 H H SO₂Me SO₂CHF₂ CF₃ Me Me H H 1 H H SO₂Me NH₂ CF₃ Me Me H H 1H H SO₂Me NHMe CF₃ Me Me H H 1 H H SO₂Me NMe₂ CF₃ Me Me H H 1 H H SO₂MeNHEt CF₃ Me Me H H 1 H H SO₂Me NEt₂ CF₃ Me Me H H 1 H H SO₂Me NHPh CF₃Me Me H H 1 H H SO₂Me N(Me)Ph CF₃ Me Me H H 1 H H SO₂Me CN CF₃ Me Me H H1 H H NH₂ F CF₃ Me Me H H 1 H H NH₂ Cl CF₃ Me Me H H 1 H H NH₂ OH CF₃ MeMe H H 1 H H NH₂ OMe CF₃ Me Me H H 1 H H NH₂ OEt CF₃ Me Me H H 1 H H NH₂OPr-i CF₃ Me Me H H 1 H H NH₂ OPr CF₃ Me Me H H 1 H H NH₂ OBu-t CF₃ MeMe H H 1 H H NH₂ OCH₂Pr-c CF₃ Me Me H H 1 H H NH₂ OCH₂Bu-c CF₃ Me Me H H1 H H NH₂ OCH₂Pen-c CF₃ Me Me H H 1 H H NH₂ OCH₂Hex-c CF₃ Me Me H H 1 HH NH₂ OPen-c CF₃ Me Me H H 1 H H NH₂ OHex-c CF₃ Me Me H H 1 H H NH₂OCH₂Ph CF₃ Me Me H H 1 H H NH₂ OPh CF₃ Me Me H H 1 H H NH₂ OCHF₂ CF₃ MeMe H H 1 H H NH₂ SH CF₃ Me Me H H 1 H H NH₂ SMe CF₃ Me Me H H 1 H H NH₂SO₂Me CF₃ Me Me H H 1 H H NH₂ SEt CF₃ Me Me H H 1 H H NH₂ SO₂Et CF₃ MeMe H H 1 H H NH₂ SPr-i CF₃ Me Me H H 1 H H NH₂ SO₂Pr-i CF₃ Me Me H H 1 HH NH₂ SPh CF₃ Me Me H H 1 H H NH₂ SO₂Ph CF₃ Me Me H H 1 H H NH₂ SCHF₂CF₃ Me Me H H 1 H H NH₂ SO₂CHF₂ CF₃ Me Me H H 1 H H NH₂ NH₂ CF₃ Me Me HH 1 H H NH₂ NHMe CF₃ Me Me H H 1 H H NH₂ NMe₂ CF₃ Me Me H H 1 H H NH₂NHEt CF₃ Me Me H H 1 H H NH₂ NEt₂ CF₃ Me Me H H 1 H H NH₂ NHPh CF₃ Me MeH H 1 H H NH₂ N(Me)Ph CF₃ Me Me H H 1 H H NH₂ CN CF₃ H H H H 1 H H H OMeCF₃ H H H H 1 H H H OEt CF₃ Me H H H 1 H H H OMe CF₃ Me H H H 1 H H HOEt CF₃ Me H Me H 1 H H H OMe CF₃ Me H Me H 1 H H H OEt CF₃ Me Me H H 1Me H H OMe CF₃ Me Me H H 1 Me H H OEt CF₃ Me Me H H 1 Et H H OMe CF₃ MeMe H H 1 Et H H OEt CF₃ Me Me H H 1 Pr-i H H H CF₃ Me Me H H 1 Pr-i H HOMe CF₃ Me Me H H 1 Pr-i H H OEt CF₃ Me Me H H 1 Me Me H OMe CF₃ Me Me HH 1 Me Me H OEt CF₃ Me Et H H 1 H H H OMe CF₃ Me Et H H 1 H H H OEt CF₃Et Et H H 1 H H H OMe CF₃ Et Et H H 1 H H H OEt CF₃ Me Pr-i H H 1 H H HOMe CF₃ Me Pr-i H H 1 H H H OEt CF₃ Me Pr H H 1 H H H OMe CF₃ Me Pr H H1 H H H OEt CF₃ Me Pr-c H H 1 H H H OMe CF₃ Me Pr-c H H 1 H H H OEt CF₃Me CH₂Pr-c H H 1 H H H OMe CF₃ Me CH₂Pr-c H H 1 H H H OEt CF₃ —(CH₂)₂— HH 1 H H H OMe CF₃ —(CH₂)₂— H H 1 H H H OEt CF₃ —(CH₂)₃— H H 1 H H H OMeCF₃ —(CH₂)₃— H H 1 H H H OEt CF₃ —(CH₂)₄— H H 1 H H H OMe CF₃ —(CH₂)₄— HH 1 H H H OEt CF₃ —(CH₂)₅— H H 1 H H H OMe CF₃ —(CH₂)₅— H H 1 H H H OEtCF₃ H —(CH₂)₃— H 1 H H H OMe CF₃ H —(CH₂)₃— H 1 H H H OEt CF₃ H —(CH₂)₄—H 1 H H H OMe CF₃ H —(CH₂)₄— H 1 H H H OEt CF₃ H —(CH₂)₅— H 1 H H H OMeCF₃ H —(CH₂)₅— H 1 H H H OEt CF₃ H —(CH₂)₆— H 1 H H H OMe CF₃ H —(CH₂)₆—H 1 H H H OEt CF₃ Me Me H H 0 H H H Cl Cl Me Me H H 0 H H H OH Cl Me MeH H 0 H H H OMe Cl Me Me H H 0 H H H OEt Cl Me Me H H 0 H H H OPr-i ClMe Me H H 0 H H H OPr Cl Me Me H H 0 H H H OBu-t Cl Me Me H H 0 H H HOCH₂Pr-c Cl Me Me H H 0 H H H OCH₂Bu-c Cl Me Me H H 0 H H H OCH₂Pen-c ClMe Me H H 0 H H H OCH₂Hex-c Cl Me Me H H 0 H H H OPen-c Cl Me Me H H 0 HH H OHex-c Cl Me Me H H 0 H H H OCH₂Ph Cl Me Me H H 0 H H H OPh Cl Me MeH H 0 H H H OCHF₂ Cl Me Me H H 0 H H H SH Cl Me Me H H 0 H H H SMe Cl MeMe H H 0 H H H SO₂Me Cl Me Me H H 0 H H H SEt Cl Me Me H H 0 H H H SO₂EtCl Me Me H H 0 H H H SPr-i Cl Me Me H H 0 H H H SO₂Pr-i Cl Me Me H H 0 HH H SPh Cl Me Me H H 0 H H H SO₂Ph Cl Me Me H H 0 H H H SCHF₂ Cl Me Me HH 0 H H H SO₂CHF₂ Cl Me Me H H 0 H H H NH₂ Cl Me Me H H 0 H H H NHMe ClMe Me H H 0 H H H NMe₂ Cl Me Me H H 0 H H H NHEt Cl Me Me H H 0 H H HNEt₂ Cl Me Me H H 0 H H H NHPh Cl Me Me H H 0 H H H N(Me)Ph Cl Me Me H H0 H H H CN Cl Me Me H H 0 H H H F Me Me Me H H 0 H H H Cl Me Me Me H H 0H H H OH Me Me Me H H 0 H H H OMe Me Me Me H H 0 H H H OEt Me Me Me H H0 H H H OPr-i Me Me Me H H 0 H H H OPr Me Me Me H H 0 H H H OBu-t Me MeMe H H 0 H H H OCH₂Pr-c Me Me Me H H 0 H H H OCH₂Bu-c Me Me Me H H 0 H HH OCH₂Pen-c Me Me Me H H 0 H H H OCH₂Hex-c Me Me Me H H 0 H H H OPen-cMe Me Me H H 0 H H H OHex-c Me Me Me H H 0 H H H OCH₂Ph Me Me Me H H 0 HH H OPh Me Me Me H H 0 H H H OCHF₂ Me Me Me H H 0 H H H SH Me Me Me H H0 H H H SMe Me Me Me H H 0 H H H SO₂Me Me Me Me H H 0 H H H SEt Me Me MeH H 0 H H H SO₂Et Me Me Me H H 0 H H H SPr-i Me Me Me H H 0 H H HSO₂Pr-i Me Me Me H H 0 H H H SPh Me Me Me H H 0 H H H SO₂Ph Me Me Me H H0 H H H SCHF₂ Me Me Me H H 0 H H H SO₂CHF₂ Me Me Me H H 0 H H H NH₂ MeMe Me H H 0 H H H NHMe Me Me Me H H 0 H H H NMe₂ Me Me Me H H 0 H H HNHEt Me Me Me H H 0 H H H NEt₂ Me Me Me H H 0 H H H NHPh Me Me Me H H 0H H H N(Me)Ph Me Me Me H H 0 H H H CN Me Me Me H H 0 H H H F Pr-i Me MeH H 0 H H H Cl Pr-i Me Me H H 0 H H H OH Pr-i Me Me H H 0 H H H OMe Pr-iMe Me H H 0 H H H OEt Pr-i Me Me H H 0 H H H OPr-i Pr-i Me Me H H 0 H HH OPr Pr-i Me Me H H 0 H H H OBu-t Pr-i Me Me H H 0 H H H OCH₂Pr-c Pr-iMe Me H H 0 H H H OCH₂Bu-c Pr-i Me Me H H 0 H H H OCH₂Pen-c Pr-i Me Me HH 0 H H H OCH₂Hex-c Pr-i Me Me H H 0 H H H OPen-c Pr-i Me Me H H 0 H H HOHex-c Pr-i Me Me H H 0 H H H OCH₂Ph Pr-i Me Me H H 0 H H H OPh Pr-i MeMe H H 0 H H H OCHF₂ Pr-i Me Me H H 0 H H H SH Pr-i Me Me H H 0 H H HSMe Pr-i Me Me H H 0 H H H SO₂Me Pr-i Me Me H H 0 H H H SEt Pr-i Me Me HH 0 H H H SO₂Et Pr-i Me Me H H 0 H H H SPr-i Pr-i Me Me H H 0 H H HSO₂Pr-i Pr-i Me Me H H 0 H H H SPh Pr-i Me Me H H 0 H H H SO₂Ph Pr-i MeMe H H 0 H H H SCHF₂ Pr-i Me Me H H 0 H H H SO₂CHF₂ Pr-i Me Me H H 0 H HH NH₂ Pr-i Me Me H H 0 H H H NHMe Pr-i Me Me H H 0 H H H NMe₂ Pr-i Me MeH H 0 H H H NHEt Pr-i Me Me H H 0 H H H NEt₂ Pr-i Me Me H H 0 H H H NHPhPr-i Me Me H H 0 H H H N(Me)Ph Pr-i Me Me H H 0 H H H CN Pr-i Me Me H H0 H H H F Pr-c Me Me H H 0 H H H Cl Pr-c Me Me H H 0 H H H OH Pr-c Me MeH H 0 H H H OMe Pr-c Me Me H H 0 H H H OEt Pr-c Me Me H H 0 H H H OPr-iPr-c Me Me H H 0 H H H OPr Pr-c Me Me H H 0 H H H OBu-t Pr-c Me Me H H 0H H H OCH₂Pr-c Pr-c Me Me H H 0 H H H OCH₂Bu-c Pr-c Me Me H H 0 H H HOCH₂Pen-c Pr-c Me Me H H 0 H H H OCH₂Hex-c Pr-c Me Me H H 0 H H H OPen-cPr-c Me Me H H 0 H H H OHex-c Pr-c Me Me H H 0 H H H OCH₂Ph Pr-c Me Me HH 0 H H H OPh Pr-c Me Me H H 0 H H H OCHF₂ Pr-c Me Me H H 0 H H H SHPr-c Me Me H H 0 H H H SMe Pr-c Me Me H H 0 H H H SO₂Me Pr-c Me Me H H 0H H H SEt Pr-c Me Me H H 0 H H H SO₂Et Pr-c Me Me H H 0 H H H SPr-i Pr-cMe Me H H 0 H H H SO₂Pr-i Pr-c Me Me H H 0 H H H SPh Pr-c Me Me H H 0 HH H SO₂Ph Pr-c Me Me H H 0 H H H SCHF₂ Pr-c Me Me H H 0 H H H SO₂CHF₂Pr-c Me Me H H 0 H H H NH₂ Pr-c Me Me H H 0 H H H NHMe Pr-c Me Me H H 0H H H NMe₂ Pr-c Me Me H H 0 H H H NHEt Pr-c Me Me H H 0 H H H NEt₂ Pr-cMe Me H H 0 H H H NHPh Pr-c Me Me H H 0 H H H N(Me)Ph Pr-c Me Me H H 0 HH H CN Pr-c Me Me H H 0 H H H F CHF₂ Me Me H H 0 H H H Cl CHF₂ Me Me H H0 H H H OH CHF₂ Me Me H H 0 H H H OMe CHF₂ Me Me H H 0 H H H OEt CHF₂ MeMe H H 0 H H H OPr-i CHF₂ Me Me H H 0 H H H OPr CHF₂ Me Me H H 0 H H HOBu-t CHF₂ Me Me H H 0 H H H OCH₂Pr-c CHF₂ Me Me H H 0 H H H OCH₂Bu-cCHF₂ Me Me H H 0 H H H OCH₂Pen-c CHF₂ Me Me H H 0 H H H OCH₂Hex-c CHF₂Me Me H H 0 H H H OPen-c CHF₂ Me Me H H 0 H H H OHex-c CHF₂ Me Me H H 0H H H OCH₂Ph CHF₂ Me Me H H 0 H H H OPh CHF₂ Me Me H H 0 H H H OCHF₂CHF₂ Me Me H H 0 H H H SH CHF₂ Me Me H H 0 H H H SMe CHF₂ Me Me H H 0 HH H SO₂Me CHF₂ Me Me H H 0 H H H SEt CHF₂ Me Me H H 0 H H H SO₂Et CHF₂Me Me H H 0 H H H SPr-i CHF₂ Me Me H H 0 H H H SO₂Pr-i CHF₂ Me Me H H 0H H H SPh CHF₂ Me Me H H 0 H H H SO₂Ph CHF₂ Me Me H H 0 H H H SCHF₂ CHF₂Me Me H H 0 H H H SO₂CHF₂ CHF₂ Me Me H H 0 H H H NH₂ CHF₂ Me Me H H 0 HH H NHMe CHF₂ Me Me H H 0 H H H NMe₂ CHF₂ Me Me H H 0 H H H NHEt CHF₂ MeMe H H 0 H H H NEt₂ CHF₂ Me Me H H 0 H H H NHPh CHF₂ Me Me H H 0 H H HN(Me)Ph CHF₂ Me Me H H 0 H H H CN CHF₂ Me Me H H 0 H H H F CF₃ Me Me H H0 H H H Cl CF₃ Me Me H H 0 H H H OH CF₃ Me Me H H 0 H H H OMe CF₃ Me MeH H 0 H H H OEt CF₃ Me Me H H 0 H H H OPr-i CF₃ Me Me H H 0 H H H OPrCF₃ Me Me H H 0 H H H OBu-t CF₃ Me Me H H 0 H H H OCH₂Pr-c CF₃ Me Me H H0 H H H OCH₂Bu-c CF₃ Me Me H H 0 H H H OCH₂Pen-c CF₃ Me Me H H 0 H H HOCH₂Hex-c CF₃ Me Me H H 0 H H H OPen-c CF₃ Me Me H H 0 H H H OHex-c CF₃Me Me H H 0 H H H OCH₂Ph CF₃ Me Me H H 0 H H H OPh CF₃ Me Me H H 0 H H HOCHF₂ CF₃ Me Me H H 0 H H H SH CF₃ Me Me H H 0 H H H SMe CF₃ Me Me H H 0H H H SO₂Me CF₃ Me Me H H 0 H H H SEt CF₃ Me Me H H 0 H H H SO₂Et CF₃ MeMe H H 0 H H H SPr-i CF₃ Me Me H H 0 H H H SO₂Pr-i CF₃ Me Me H H 0 H H HSPh CF₃ Me Me H H 0 H H H SO₂Ph CF₃ Me Me H H 0 H H H SCHF₂ CF₃ Me Me HH 0 H H H SO₂CHF₂ CF₃ Me Me H H 0 H H H NH₂ CF₃ Me Me H H 0 H H H NHMeCF₃ Me Me H H 0 H H H NMe₂ CF₃ Me Me H H 0 H H H NHEt CF₃ Me Me H H 0 HH H NEt₂ CF₃ Me Me H H 0 H H H NHPh CF₃ Me Me H H 0 H H H N(Me)Ph CF₃ MeMe H H 0 H H H CN CF₃ Me Me H H 0 H H H F OMe Me Me H H 0 H H H OH OMeMe Me H H 0 H H H OMe OMe Me Me H H 0 H H H OEt OMe Me Me H H 0 H H HOPr-i OMe Me Me H H 0 H H H OPr OMe Me Me H H 0 H H H OBu-t OMe Me Me HH 0 H H H OCH₂Pr-c OMe Me Me H H 0 H H H OCH₂Bu-c OMe Me Me H H 0 H H HOCH₂Pen-c OMe Me Me H H 0 H H H OCH₂Hex-c OMe Me Me H H 0 H H H OPen-cOMe Me Me H H 0 H H H OHex-c OMe Me Me H H 0 H H H OCH₂Ph OMe Me Me H H0 H H H OPh OMe Me Me H H 0 H H H OCHF₂ OMe Me Me H H 0 H H H SH OMe MeMe H H 0 H H H SMe OMe Me Me H H 0 H H H SO₂Me OMe Me Me H H 0 H H H SEtOMe Me Me H H 0 H H H SO₂Et OMe Me Me H H 0 H H H SPr-i OMe Me Me H H 0H H H SO₂Pr-i OMe Me Me H H 0 H H H SPh OMe Me Me H H 0 H H H SO₂Ph OMeMe Me H H 0 H H H SCHF₂ OMe Me Me H H 0 H H H SO₂CHF₂ OMe Me Me H H 0 HH H NH₂ OMe Me Me H H 0 H H H NHMe OMe Me Me H H 0 H H H NMe₂ OMe Me MeH H 0 H H H NHEt OMe Me Me H H 0 H H H NEt₂ OMe Me Me H H 0 H H H NHPhOMe Me Me H H 0 H H H N(Me)Ph OMe Me Me H H 0 H H H CN OMe Me Me H H 0 HH H F OPh Me Me H H 0 H H H OH OPh Me Me H H 0 H H H OMe OPh Me Me H H 0H H H OEt OPh Me Me H H 0 H H H OPr-i OPh Me Me H H 0 H H H OPr OPh MeMe H H 0 H H H OBu-t OPh Me Me H H 0 H H H OCH₂Pr-c OPh Me Me H H 0 H HH OCH₂Bu-c OPh Me Me H H 0 H H H OCH₂Pen-c OPh Me Me H H 0 H H HOCH₂Hex-c OPh Me Me H H 0 H H H OPen-c OPh Me Me H H 0 H H H OHex-c OPhMe Me H H 0 H H H OCH₂Ph OPh Me Me H H 0 H H H OPh OPh Me Me H H 0 H H HOCHF₂ OPh Me Me H H 0 H H H SH OPh Me Me H H 0 H H H SMe OPh Me Me H H 0H H H SO₂Me OPh Me Me H H 0 H H H SEt OPh Me Me H H 0 H H H SO₂Et OPh MeMe H H 0 H H H SPr-i OPh Me Me H H 0 H H H SO₂Pr-i OPh Me Me H H 0 H H HSPh OPh Me Me H H 0 H H H SO₂Ph OPh Me Me H H 0 H H H SCHF₂ OPh Me Me HH 0 H H H SO₂CHF₂ OPh Me Me H H 0 H H H NH₂ OPh Me Me H H 0 H H H NHMeOPh Me Me H H 0 H H H NMe₂ OPh Me Me H H 0 H H H NHEt OPh Me Me H H 0 HH H NEt₂ OPh Me Me H H 0 H H H NHPh OPh Me Me H H 0 H H H N(Me)Ph OPh MeMe H H 0 H H H CN OPh Me Me H H 0 H H H F OCHF₂ Me Me H H 0 H H H OHOCHF₂ Me Me H H 0 H H H OMe OCHF₂ Me Me H H 0 H H H OEt OCHF₂ Me Me H H0 H H H OPr-i OCHF₂ Me Me H H 0 H H H OPr OCHF₂ Me Me H H 0 H H H OBu-tOCHF₂ Me Me H H 0 H H H OCH₂Pr-c OCHF₂ Me Me H H 0 H H H OCH₂Bu-c OCHF₂Me Me H H 0 H H H OCH₂Pen-c OCHF₂ Me Me H H 0 H H H OCH₂Hex-c OCHF₂ MeMe H H 0 H H H OPen-c OCHF₂ Me Me H H 0 H H H OHex-c OCHF₂ Me Me H H 0 HH H OCH₂Ph OCHF₂ Me Me H H 0 H H H OPh OCHF₂ Me Me H H 0 H H H OCHF₂OCHF₂ Me Me H H 0 H H H SH OCHF₂ Me Me H H 0 H H H SMe OCHF₂ Me Me H H 0H H H SO₂Me OCHF₂ Me Me H H 0 H H H SEt OCHF₂ Me Me H H 0 H H H SO₂EtOCHF₂ Me Me H H 0 H H H SPr-i OCHF₂ Me Me H H 0 H H H SO₂Pr-i OCHF₂ MeMe H H 0 H H H SPh OCHF₂ Me Me H H 0 H H H SO₂Ph OCHF₂ Me Me H H 0 H H HSCHF₂ OCHF₂ Me Me H H 0 H H H SO₂CHF₂ OCHF₂ Me Me H H 0 H H H NH₂ OCHF₂Me Me H H 0 H H H NHMe OCHF₂ Me Me H H 0 H H H NMe₂ OCHF₂ Me Me H H 0 HH H NHEt OCHF₂ Me Me H H 0 H H H NEt₂ OCHF₂ Me Me H H 0 H H H NHPh OCHF₂Me Me H H 0 H H H N(Me)Ph OCHF₂ Me Me H H 0 H H H CN OCHF₂ Me Me H H 0 HH Me F CF₃ Me Me H H 0 H H Me Cl CF₃ Me Me H H 0 H H Me OH CF₃ Me Me H H0 H H Me OMe CF₃ Me Me H H 0 H H Me OEt CF₃ Me Me H H 0 H H Me OPr-i CF₃Me Me H H 0 H H Me OPr CF₃ Me Me H H 0 H H Me OBu-t CF₃ Me Me H H 0 H HMe OCH₂Pr-c CF₃ Me Me H H 0 H H Me OCH₂Bu-c CF₃ Me Me H H 0 H H MeOCH₂Pen-c CF₃ Me Me H H 0 H H Me OCH₂Hex-c CF₃ Me Me H H 0 H H Me OPen-cCF₃ Me Me H H 0 H H Me OHex-c CF₃ Me Me H H 0 H H Me OCH₂Ph CF₃ Me Me HH 0 H H Me OPh CF₃ Me Me H H 0 H H Me OCHF₂ CF₃ Me Me H H 0 H H Me SHCF₃ Me Me H H 0 H H Me SMe CF₃ Me Me H H 0 H H Me SO₂Me CF₃ Me Me H H 0H H Me SEt CF₃ Me Me H H 0 H H Me SO₂Et CF₃ Me Me H H 0 H H Me SPr-i CF₃Me Me H H 0 H H Me SO₂Pr-i CF₃ Me Me H H 0 H H Me SPh CF₃ Me Me H H 0 HH Me SO₂Ph CF₃ Me Me H H 0 H H Me SCHF₂ CF₃ Me Me H H 0 H H Me SO₂CHF₂CF₃ Me Me H H 0 H H Me NH₂ CF₃ Me Me H H 0 H H Me NHMe CF₃ Me Me H H 0 HH Me NMe₂ CF₃ Me Me H H 0 H H Me NHEt CF₃ Me Me H H 0 H H Me NEt₂ CF₃ MeMe H H 0 H H Me NHPh CF₃ Me Me H H 0 H H Me N(Me)Ph CF₃ Me Me H H 0 H HMe CN CF₃ Me Me H H 0 H H OMe F CF₃ Me Me H H 0 H H OMe Cl CF₃ Me Me H H0 H H OMe OH CF₃ Me Me H H 0 H H OMe OMe CF₃ Me Me H H 0 H H OMe OEt CF₃Me Me H H 0 H H OMe OPr-i CF₃ Me Me H H 0 H H OMe OPr CF₃ Me Me H H 0 HH OMe OBu-t CF₃ Me Me H H 0 H H OMe OCH₂Pr-c CF₃ Me Me H H 0 H H OMeOCH₂Bu-c CF₃ Me Me H H 0 H H OMe OCH₂Pen-c CF₃ Me Me H H 0 H H OMeOCH₂Hex-c CF₃ Me Me H H 0 H H OMe OPen-c CF₃ Me Me H H 0 H H OMe OHex-cCF₃ Me Me H H 0 H H OMe OCH₂Ph CF₃ Me Me H H 0 H H OMe OPh CF₃ Me Me H H0 H H OMe OCHF₂ CF₃ Me Me H H 0 H H OMe SH CF₃ Me Me H H 0 H H OMe SMeCF₃ Me Me H H 0 H H OMe SO₂Me CF₃ Me Me H H 0 H H OMe SEt CF₃ Me Me H H0 H H OMe SO₂Et CF₃ Me Me H H 0 H H OMe SPr-i CF₃ Me Me H H 0 H H OMeSO₂Pr-i CF₃ Me Me H H 0 H H OMe SPh CF₃ Me Me H H 0 H H OMe SO₂Ph CF₃ MeMe H H 0 H H OMe SCHF₂ CF₃ Me Me H H 0 H H OMe SO₂CHF₂ CF₃ Me Me H H 0 HH OMe NH₂ CF₃ Me Me H H 0 H H OMe NHMe CF₃ Me Me H H 0 H H OMe NMe₂ CF₃Me Me H H 0 H H OMe NHEt CF₃ Me Me H H 0 H H OMe NEt₂ CF₃ Me Me H H 0 HH OMe NHPh CF₃ Me Me H H 0 H H OMe N(Me)Ph CF₃ Me Me H H 0 H H OMe CNCF₃ Me Me H H 0 H H SMe F CF₃ Me Me H H 0 H H SMe Cl CF₃ Me Me H H 0 H HSMe OH CF₃ Me Me H H 0 H H SMe OMe CF₃ Me Me H H 0 H H SMe OEt CF₃ Me MeH H 0 H H SMe OPr-i CF₃ Me Me H H 0 H H SMe OPr CF₃ Me Me H H 0 H H SMeOBu-t CF₃ Me Me H H 0 H H SMe OCH₂Pr-c CF₃ Me Me H H 0 H H SMe OCH₂Bu-cCF₃ Me Me H H 0 H H SMe OCH₂Pen-c CF₃ Me Me H H 0 H H SMe OCH₂Hex-c CF₃Me Me H H 0 H H SMe OPen-c CF₃ Me Me H H 0 H H SMe OHex-c CF₃ Me Me H H0 H H SMe OCH₂Ph CF₃ Me Me H H 0 H H SMe OPh CF₃ Me Me H H 0 H H SMeOCHF₂ CF₃ Me Me H H 0 H H SMe SH CF₃ Me Me H H 0 H H SMe SMe CF₃ Me Me HH 0 H H SMe SO₂Me CF₃ Me Me H H 0 H H SMe SEt CF₃ Me Me H H 0 H H SMeSO₂Et CF₃ Me Me H H 0 H H SMe SPr-i CF₃ Me Me H H 0 H H SMe SO₂Pr-i CF₃Me Me H H 0 H H SMe SPh CF₃ Me Me H H 0 H H SMe SO₂Ph CF₃ Me Me H H 0 HH SMe SCHF₂ CF₃ Me Me H H 0 H H SMe SO₂CHF₂ CF₃ Me Me H H 0 H H SMe NH₂CF₃ Me Me H H 0 H H SMe NHMe CF₃ Me Me H H 0 H H SMe NMe₂ CF₃ Me Me H H0 H H SMe NHEt CF₃ Me Me H H 0 H H SMe NEt₂ CF₃ Me Me H H 0 H H SMe NHPhCF₃ Me Me H H 0 H H SMe N(Me)Ph CF₃ Me Me H H 0 H H SMe CN CF₃ Me Me H H0 H H SO₂Me F CF₃ Me Me H H 0 H H SO₂Me Cl CF₃ Me Me H H 0 H H SO₂Me OHCF₃ Me Me H H 0 H H SO₂Me OMe CF₃ Me Me H H 0 H H SO₂Me OEt CF₃ Me Me HH 0 H H SO₂Me OPr-i CF₃ Me Me H H 0 H H SO₂Me OPr CF₃ Me Me H H 0 H HSO₂Me OBu-t CF₃ Me Me H H 0 H H SO₂Me OCH₂Pr-c CF₃ Me Me H H 0 H H SO₂MeOCH₂Bu-c CF₃ Me Me H H 0 H H SO₂Me OCH₂Pen-c CF₃ Me Me H H 0 H H SO₂MeOCH₂Hex-c CF₃ Me Me H H 0 H H SO₂Me OPen-c CF₃ Me Me H H 0 H H SO₂MeOHex-c CF₃ Me Me H H 0 H H SO₂Me OCH₂Ph CF₃ Me Me H H 0 H H SO₂Me OPhCF₃ Me Me H H 0 H H SO₂Me OCHF₂ CF₃ Me Me H H 0 H H SO₂Me SH CF₃ Me Me HH 0 H H SO₂Me SMe CF₃ Me Me H H 0 H H SO₂Me SO₂Me CF₃ Me Me H H 0 H HSO₂Me SEt CF₃ Me Me H H 0 H H SO₂Me SO₂Et CF₃ Me Me H H 0 H H SO₂MeSPr-i CF₃ Me Me H H 0 H H SO₂Me SO₂Pr-i CF₃ Me Me H H 0 H H SO₂Me SPhCF₃ Me Me H H 0 H H SO₂Me SO₂Ph CF₃ Me Me H H 0 H H SO₂Me SCHF₂ CF₃ MeMe H H 0 H H SO₂Me SO₂CHF₂ CF₃ Me Me H H 0 H H SO₂Me NH₂ CF₃ Me Me H H 0H H SO₂Me NHMe CF₃ Me Me H H 0 H H SO₂Me NMe₂ CF₃ Me Me H H 0 H H SO₂MeNHEt CF₃ Me Me H H 0 H H SO₂Me NEt₂ CF₃ Me Me H H 0 H H SO₂Me NHPh CF₃Me Me H H 0 H H SO₂Me N(Me)Ph CF₃ Me Me H H 0 H H SO₂Me CN CF₃ Me Me H H0 H H NH₂ F CF₃ Me Me H H 0 H H NH₂ Cl CF₃ Me Me H H 0 H H NH₂ OH CF₃ MeMe H H 0 H H NH₂ OMe CF₃ Me Me H H 0 H H NH₂ OEt CF₃ Me Me H H 0 H H NH₂OPr-i CF₃ Me Me H H 0 H H NH₂ OPr CF₃ Me Me H H 0 H H NH₂ OBu-t CF₃ MeMe H H 0 H H NH₂ OCH₂Pr-c CF₃ Me Me H H 0 H H NH₂ OCH₂Bu-c CF₃ Me Me H H0 H H NH₂ OCH₂Pen-c CF₃ Me Me H H 0 H H NH₂ OCH₂Hex-c CF₃ Me Me H H 0 HH NH₂ OPen-c CF₃ Me Me H H 0 H H NH₂ OHex-c CF₃ Me Me H H 0 H H NH₂OCH₂Ph CF₃ Me Me H H 0 H H NH₂ OPh CF₃ Me Me H H 0 H H NH₂ OCHF₂ CF₃ MeMe H H 0 H H NH₂ SH CF₃ Me Me H H 0 H H NH₂ SMe CF₃ Me Me H H 0 H H NH₂SO₂Me CF₃ Me Me H H 0 H H NH₂ SEt CF₃ Me Me H H 0 H H NH₂ SO₂Et CF₃ MeMe H H 0 H H NH₂ SPr-i CF₃ Me Me H H 0 H H NH₂ SO₂Pr-i CF₃ Me Me H H 0 HH NH₂ SPh CF₃ Me Me H H 0 H H NH₂ SO₂Ph CF₃ Me Me H H 0 H H NH₂ SCHF₂CF₃ Me Me H H 0 H H NH₂ SO₂CHF₂ CF₃ Me Me H H 0 H H NH₂ NH₂ CF₃ Me Me HH 0 H H NH₂ NHMe CF₃ Me Me H H 0 H H NH₂ NMe₂ CF₃ Me Me H H 0 H H NH₂NHEt CF₃ Me Me H H 0 H H NH₂ NEt₂ CF₃ Me Me H H 0 H H NH₂ NHPh CF₃ Me MeH H 0 H H NH₂ N(Me)Ph CF₃ Me Me H H 0 H H NH₂ CN CF₃ H H H H 0 H H H OMeCF₃ H H H H 0 H H H OEt CF₃ Me H H H 0 H H H OMe CF₃ Me H H H 0 H H HOEt CF₃ Me H Me H 0 H H H OMe CF₃ Me H Me H 0 H H H OEt CF₃ Me Me H H 0Me H H OMe CF₃ Me Me H H 0 Me H H OEt CF₃ Me Me H H 0 Et H H OMe CF₃ MeMe H H 0 Et H H OEt CF₃ Me Me H H 0 Pr-i H H H CF₃ Me Me H H 0 Pr-i H HOMe CF₃ Me Me H H 0 Pr-i H H OEt CF₃ Me Me H H 0 Me Me H OMe CF₃ Me Me HH 0 Me Me H OEt CF₃ Me Et H H 0 H H H OMe CF₃ Me Et H H 0 H H H OEt CF₃Et Et H H 0 H H H OMe CF₃ Et Et H H 0 H H H OEt CF₃ Me Pr-i H H 0 H H HOMe CF₃ Me Pr-i H H 0 H H H OEt CF₃ Me Pr H H 0 H H H OMe CF₃ Me Pr H H0 H H H OEt CF₃ Me Pr-c H H 0 H H H OMe CF₃ Me Pr-c H H 0 H H H OEt CF₃Me CH₂Pr-c H H 0 H H H OMe CF₃ Me CH₂Pr-c H H 0 H H H OEt CF₃ —(CH₂)₂— HH 0 H H H OMe CF₃ —(CH₂)₂— H H 0 H H H OEt CF₃ —(CH₂)₃— H H 0 H H H OMeCF₃ —(CH₂)₃— H H 0 H H H OEt CF₃ —(CH₂)₄— H H 0 H H H OMe CF₃ —(CH₂)₄— HH 0 H H H OEt CF₃ —(CH₂)₅— H H 0 H H H OMe CF₃ —(CH₂)₅— H H 0 H H H OEtCF₃ H —(CH₂)₃— H 0 H H H OMe CF₃ H —(CH₂)₃— H 0 H H H OEt CF₃ H —(CH₂)₄—H 0 H H H OMe CF₃ H —(CH₂)₄— H 0 H H H OEt CF₃ H —(CH₂)₅— H 0 H H H OMeCF₃ H —(CH₂)₅— H 0 H H H OEt CF₃ H —(CH₂)₆— H 0 H H H OMe CF₃ H —(CH₂)₆—H 0 H H H OEt CF₃

TABLE 9

R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ Me Me H H 2 H H Pyridin-2-yl Me Me H H 2 H HPyridin-2-yl 1-oxide Me Me H H 2 H H Pyridin-4-yl Me Me H H 2 H HPyridin-4-yl 1-oxide Me Me H H 2 H H 1,2,4-Oxadiazol-3-yl Me Me H H 2 HH 3-Phenyl-1,2,4-oxadiazol-5-yl Me Me H H 2 H H3-Benzyl-1,2,4-oxadiazol-5-yl Me Me H H 2 H H 2-Chlorothiazol-4-yl Me MeH H 2 H H 5-Trifluoromethyl-1,3,4-thiadiazol-2-yl Me Me H H 2 H H1,4-Dimethylimidazol-5-yl Me Me H H 2 H H1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl Me Me H H 2 H H1-Diflluoromethyl-1,2,4-triazol-3-yl Me Me H H 2 H H1-Diflluoromethyl-1,2,4-triazol-5-yl Me Me H H 2 H H4-Diflluoromethyl-1,2,4-triazo1-3-yl Me Me H H 2 H H4,6-Dimethoxypyrimidin-2-yl Me Me H H 2 H H 4,6-Diethoxypyrimidin-2-ylMe Me H H 2 H H 4,6-Dimethylpyrimidin-2-yl Me Me H H 2 H H4-Chloro-6-methylpyrimidin-2-yl Me Me H H 2 H H4-Methoxy-6-methylpyrimidin-2-yl Me Me H H 2 H H4-Difluoromethoxy-6-metbylpyrimidin-2-yl Me Me H H 2 H H4-Phenoxy-6-methylpyrimidin-2-yl Me Me H H 2 H H4-Chloro-6-trifluoromethylpyrimidin-2-yl Me Me H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-2-yl Me Me H H 2 H H4-Difluoromethoxy-6-trifluoromethylpyrimidin-2-yl Me Me H H 2 H H4-Phenoxy-6-trifluoromethylpyrimidin-2-yl H H H H 2 H H4,6-Dimethoxypyrimidin-2-yl Me H H H 2 H H 4,6-Dimethoxypyrimidin-2-ylMe H Me H 2 H H 4,6-Dimethoxypyrimidin-2-yl Me Me H H 2 Me H4,6-Dimethoxypyrimidin-2-yl Me Me H H 2 Et H 4,6-Dimethoxypyrimidin-2-ylMe Me H H 2 Pr-i H 4,6-Dimethoxypyrimidin-2-yl Me Me H H 2 Me Me4,6-Dirnetboxypyrimidin-2-yl Me Et H H 2 H H 4,6-Dimethoxypyrimidin-2-ylEt Et H H 2 H H 4,6-Dimethoxypyrimidin-2-yl Me Pr-i H H 2 H H4,6-Dimethoxypyrimidin-2-yl Me Pr H H 2 H H 4,6-Dimethoxypyrimidin-2-ylMe Pr-c H H 2 H H 4,6-Dimethoxypyrimidin-2-yl Me CH₂Pr-c H H 2 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₂— H H 2 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₃— H H 2 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₄— H H 2 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₅— H H 2 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₃— H 2 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₄— H 2 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₅— H 2 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₆— H 2 H H4,6-Dimethoxypyrimidin-2-yl Me Me H H 1 H H Pyridin-2-yl Me Me H H 1 H HPyridin-2-yl 1-oxide Me Me H H 1 H H Pyridin-4-yl Me Me H H 1 H HPyridin-4-yl 1-oxide Me Me H H 1 H H 1,2,4-Oxadiazol-3-yl Me Me H H 1 HH 3-Phenyl-1,2,4-oxadiazol-5-yl Me Me H H 1 H H3-Benzyl-1,2,4-oxadiazol-5-yl Me Me H H 1 H H 2-Chlorothiazol-4-yl Me MeH H 1 H H 5-Trifluoromethyl-1,3,4-thiadiazol-2-yl Me Me H H 1 H H1,4-Dimethylimidazol-5-yl Me Me H H 1 H H1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl Me Me H H 1 H H1-Diflluoromethyl-1,2,4-triazol-3-yl Me Me H H 1 H H1-Diflluoromethyl-1,2,4-triazol-5-yl Me Me H H 1 H H4-Diflluoromethyl-1,2,4-triazol-3-yl Me Me H H 1 H H4,6-Dimethoxypyrimidin-2-yl Me Me H H 1 H H 4,6-Diethoxypyrimidin-2-ylMe Me H H 1 H H 4,6-Dimethylpyrimidin-2-yl Me Me H H 1 H H4-Chloro-6-methylpyrimidin-2-yl Me Me H H 1 H H4-Methoxy-6-methylpyrimidin-2-yl Me Me H H 1 H H4-Difluoromethoxy-6-methylpyrimidin-2-yl Me Me H H 1 H H4-Phenoxy-6-methylpyrimidin-2-yl Me Me H H 1 H H4-Chloro-6-trifluoromethylpyrimidin-2-yl Me Me H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-2-yl Me Me H H 1 H H4-Difluoromethoxy-6-trifluoromethylpyrimidin-2-yl Me Me H H 1 H H4-Phenoxy-6-trifluoromethylpyrimidin-2-yl H H H H 1 H H4,6-Dimethoxypyrimidin-2-yl Me H H H 1 H H 4,6-Dimethoxypyrimidin-2-ylMe H Me H 1 H H 4,6-Dimethoxypyrimidin-2-yl Me Me H H 1 Me H4,6-Dimethokypyrimidin-2-yl Me Me H H 1 Et H 4,6-Dimethoxypyrimidin-2-ylMe Me H H 1 Pr-i H 4,6-Dimethoxypyrimidin-2-yl Me Me H H 1 Me Me4,6-Dimethoxypyrimidin-2-yl Me Et H H 1 H H 4,6-Dimethoxypyrimidin-2-ylEt Et H H 1 H H 4,6-Dimethoxypyrimidin-2-yl Me Pr-i H H 1 H H4,6-Dimethoxypyrimidin-2-yl Me Pr H H 1 H H 4,6-Dimethoxypyrimidin-2-ylMe Pr-c H H 1 H H 4,6-Dimethoxypyrimidin-2-yl Me CH₂Pr-c H H 1 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₂— H H 1 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₃— H H 1 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₄— H H 1 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₅— H H 1 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₃— H 1 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₄— H 1 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₅— H 1 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₆— H 1 H H4,6-Dimethoxypyrimidin-2-yl Me Me H H 0 H H Pyridin-2-yl Me Me H H 0 H HPyridin-2-yl 1-oxide Me Me H H 0 H H Pyridin-4-yl Me Me H H 0 H HPyridin-4-yl 1-oxide Me Me H H 0 H H 1,2,4-Oxadiazol-3-yl Me Me H H 0 HH 3-Phenyl-1,2,4-oxadiazol-5-yl Me Me H H 0 H H3-Benzyl-1,2,4-oxadiazol-5-yl Me Me H H 0 H H 2-Chlorothiazol-4-yl Me MeH H 0 H H 5-Trifluoromethyl-1,3,4-thiadiazol-2-yl Me Me H H 0 H H1,4-Dimethylimidazol-5-yl Me Me H H 0 H H1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl Me Me H H 0 H H1-Diflluoromethyl-1,2,4-triazol-3-yl Me Me H H 0 H H1-Diflluoromethyl-1,2,4-triazol-5-yl Me Me H H 0 H H4-Diflluoromethyl-1,2,4-triazol-3-yl Me Me H H 0 H H4,6-Dimethoxypyrimidin-2-yl Me Me H H 0 H H 4,6-Diethoxypyrimidin-2-ylMe Me H H 0 H H 4,6-Dimethylpyrimidin-2-yl Me Me H H 0 H H4-Chloro-6-methylpyrimidin-2-yl Me Me H H 0 H H4-Methoxy-6-methylpyrimidin-2-yl Me Me H H 0 H H4-Difluoromethoxy-6-methylpyrimidin-2-yl Me Me H H 0 H H4-Phenoxy-6-methylpyrimidin-2-yl Me Me H H 0 H H4-Chloro-6-trifluoromethylpyrimidin-2-yl Me Me H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-2-yl Me Me H H 0 H H4-Difluoromethoxy-6-trifluoromethylpyrimidin-2-yl Me Me H H 0 H H4-Phenoxy-6-trifluoromethylpyrimidin-2-yl H H H H 0 H H4,6-Dimethoxypyrimidin-2-yl Me H H H 0 H H 4,6-Dimethoxypyrimidin-2-ylMe H Me H 0 H H 4,6-Dimethoxypyrimidin-2-yl Me Me H H 0 Me H4,6-Dimethoxypyrimidin-2-yl Me Me H H 0 Et H 4,6-Dimethoxypyrimidin-2-ylMe Me H H 0 Pr-i H 4,6-Dimethoxypyrimidin-2-yl Me Me H H 0 Me Me4,6-Dimethoxypyrimidin-2-yl Me Et H H 0 H H 4,6-Dimethoxypyrimidin-2-ylEt Et H H 0 H H 4,6-Dimethoxypyrimidin-2-yl Me Pr-i H H 0 H H4,6-Dimethoxypyrimidin-2-yl Me Pr H H 0 H H 4,6-Dimethoxypyrimidin-2-ylMe Pr-c H H 0 H H 4,6-Dimethoxypyrimidin-2-yl Me CH₂Pr-c H H 0 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₂— H H 0 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₃— H H 0 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₄— H H 0 H H4,6-Dimethoxypyrimidin-2-yl —(CH₂)₅— H H 0 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₃— H 0 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₄— H 0 H H4,6-Dimethoxypyrimidin-2-y1 H —(CH₂)₅— H 0 H H4,6-Dimethoxypyrimidin-2-yl H —(CH₂)₆— H 0 H H4,6-Dimethoxypyrimidin-2-yl Me Et H H 2 H H Pirrol-1-yl Me Et H H 2 H HOxazol-2-yl Me Et H H 2 H H Thiazol-2-yl Me Et H H 2 H H Thiazol-4-yl MeEt H H 2 H H 1,2,3-Thiadiazol-4-yl Me Et H H 2 H H 1,2,3-Thiadiazol-5-ylMe Et H H 2 H H 1,2,4-Thiadiazol-3-yl Me Et H H 2 H H1,2,4-Thiadiazol-5-yl Me Et H H 2 H H 1,3,4-Thiadiazol-2-yl Me Et H H 2H H 1,3,4-Thiadiazol-5-yl Me Et H H 2 H H Pyridin-2-yl Me Et H H 2 H HPyridin-3-yl Me Et H H 2 H H Pyridin-4-yl Me Et H H 2 H H1H-Imidazol-2-yl Me Et H H 2 H H 1H-Imidazol-4-yl Me Et H H 2 H H1H-Imidazol-5-yl Me Et H H 2 H H 1H-1,3,4-Triazol-2-yl Me Et H H 2 H H1H-1,3,4-Triazol-5-yl

TABLE 10

R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ Me Me H H 2 H H Benzimidazol-2-yl Me Me H H 2 H HBenzothiophen-2-yl Me Me H H 2 H H 3-Chlorobenzothiophen-2-yl Me Me H H2 H H Benzotriazol-1-yl Me Me H H 2 H H 1-Methylindazol-4-yl Me Me H H 2H H Benzothiazol-2-yl Me Me H H 2 H H Benzothiophen-3-yl Me Me H H 2 H H5-Chlorobenzothiophen-3-yl Me Me H H 2 H H Benzoxazol-2-yl Me Me H H 2 HH 3-Methylbenzothiophen-2-yl Me Me H H 2 H H 3-Bromobenzothiophen-2-ylMe Me H H 2 H H Benzofuran-2-yl Me Me H H 2 H H 2-Methylbenzofuran-7-ylMe Me H H 2 H H 3-Bromobenzofuran-2-yl Me Me H H 2 H HBenzothiophen-7-yl Me Me H H 2 H H 1-Methylindazol-7-yl Me Me H H 2 H H1-Difluoromethylindazol-7-yl Me Me H H 2 H H 3-Methylbenzofuran-2-yl MeMe H H 2 H H 3-Chloro-1-methylindol-2-yl Me Me H H 1 H HBenzimidazol-2-yl Me Me H H 1 H H Benzothiophen-2-yl Me Me H H 1 H H3-Chlorobenzothiophen-2-yl Me Me H H 1 H H Benzotriazol-1-yl Me Me H H 1H H 1-Methylindazol-4-yi Me Me H H 1 H H Benzothiazol-2-yl Me Me H H 1 HH Benzothiophen-3-yl Me Me H H 1 H H 5-Chlorobenzothiophen-3-yl Me Me HH 1 H H Benzoxazol-2-yl Me Me H H 1 H H 3-Methylbenzothiophen-2-yl Me MeH H 1 H H 3-Bromobenzothiophen-2-yl Me Me H H 1 H H Benzofuran-2-yl MeMe H H 1 H H 2-Methylbenzofuran-7-yl Me Me H H 1 H H3-Bromobenzofuran-2-yl Me Me H H 1 H H Benzothiophen-7-yl Me Me H H 1 HH 1-Methylindazol-7-yl Me Me H H 1 H H 3-Methylbenzofuran-2-yl Me Me H H1 H H 3-Chloro-1-methylindol-2-yl Me Me H H 0 H H Benzimidazol-2-yl MeMe H H 0 H H Benzothiophen-2-yl Me Me H H 0 H H3-Chlorobenzothiophen-2-yl Me Me H H 0 H H Benzotriazol-1-yl Me Me H H 0H H 1 -Methylindazol-4-yl Me Me H H 0 H H Benzothiazol-2-yl Me Me H H 0H H Benzothiophen-3-yl Me Me H H 0 H H 5-Chlorobenzothiophen-3-yl Me MeH H 0 H H Benzoxazol-2-yl Me Me H H 0 H H 3-Methylbenzothiophen-2-yl MeMe H H 0 H H 3-Bromobenzothiophen-2-yl Me Me H H 0 H H Benzofuran-2-ylMe Me H H 0 H H 2-Methylbenzofuran-7-yl Me Me H H 0 H H3-Bromobenzofuran-2-yl Me Me H H 0 H H Benzothiophen-7-yl Me Me H H 0 HH 1-Methylindazol-7-yl Me Me H H 0 H H 3-Methylbenzofuran-2-yl Me Me H H0 H H 3-Chloro-1-methylindol-2-yl Me Et H H 2 H H Benzoxazol-2-yl Me EtH H 2 H H 4-Chlorobenzoxazol-2-yl Me Et H H 2 H H5-Chlorobenzoxazol-2-yl Me Et H H 2 H H 6-Chlorobenzoxazol-2-yl Me Et HH 2 H H 7-Chlorobenzoxazol-2-yl Me Et H H 2 H H 4-Fluorobenzoxazol-2-ylMe Et H H 2 H H 5-Fluorobenzoxazol-2-yl Me Et H H 2 H H6-Fluorobenzoxazol-2-yl Me Et H H 2 H H 7-Fluorobenzoxazol-2-yl Me Et HH 2 H H 4-Methylbenzoxazol-2-yl Me Et H H 2 H H 5-Methylbenzoxazol-2-ylMe Et H H 2 H H 6-Methylbenzoxazol-2-yl Me Et H H 2 H H7-Methylbenzoxazol-2-yl Me Et H H 2 H H 4-Methoxybenzoxazol-2-yl Me Et HH 2 H H 5-Methoxybenzoxazol-2-yl Me Et H H 2 H H6-Methoxybenzoxazol-2-yl Me Et H H 2 H H 7-Methoxybenzoxazol-2-yl Me EtH H 2 H H Benzothiazol-2-yl Me Et H H 2 H H 4-Chlorobenzothiazol-2-yl MeEt H H 2 H H 5-Chlorobenzothiazol-2-yl Me Et H H 2 H H6-Chlorobenzothiazol-2-yl Me Et H H 2 H H 7-Chlorobenzothiazol-2-yl MeEt H H 2 H H 4-Fluorobenzothiazol-2-yl Me Et H H 2 H H5-Fluorobenzothiazol-2-yl Me Et H H 2 H H 6-Fluorobenzothiazol-2-yl MeEt H H 2 H H 7-Fluorobenzothiazol-2-yl Me Et H H 2 H H4-Methylbenzothiazol-2-yl Me Et H H 2 H H 5-Methylbenzothiazol-2-yl MeEt H H 2 H H 6-Methylbenzothiazol-2-yl Me Et H H 2 H H7-Methylbenzothiazol-2-yl Me Et H H 2 H H 4-Methoxybenzothiazol-2-yl MeEt H H 2 H H 5-Methoxybenzothiazol-2-yl Me Et H H 2 H H6-Methoxybenzothiazol-2-yl Me Et H H 2 H H 7-Methoxybenzothiazol-2-yl MeEt H H 2 H H Qnolin-2-yl Me Et H H 2 H H Qinolin-6-yl Me Et H H 2 H HQuinoxalin-2-yl Me Et H H 2 H H Benzofuran-2-yl Me Et H H 2 H H3-Chlorobenzofuran-2-yl Me Et H H 2 H H 4-Chlorobenzofuran-2-yl Me Et HH 2 H H 5-Chlorobenzofuran-2-yl Me Et H H 2 H H 6-Chlorobenzofuran-2-ylMe Et H H 2 H H 7-Chlorobenzofuran-2-yl Me Et H H 2 H H3-Methylbenzofuran-2-yl Me Et H H 2 H H 4-Methylbenzofuran-2-yl Me Et HH 2 H H 5-Methylbenzofuran-2-yl Me Et H H 2 H H 6-Methylbenzofuran-2-ylMe Et H H 2 H H 7-Methylbenzofuran-2-yl Me Et H H 2 H H3-Methoxybenzofuran-2-yl Me Et H H 2 H H 4-Methoxybenzofuran-2-yl Me EtH H 2 H H 5-Methoxybenzofuran-2-yl Me Et H H 2 H H6-Methoxybenzofuran-2-yl Me Et H H 2 H H 7-Methoxybenzofuran-2-yl

The present compound represented by the general formula [I] can beproduced according to the processes shown below; however, the compoundcan be produced also by other processes.

<Production Process 1> Step 1 to Step 5

In the above production scheme, R¹, R² ₇ R³, R⁴, R⁵, R⁶ and Y have thesame definitions as given above; X¹ is a halogen atom; R⁷ is a C1 to C4alkyl group, an optionally substituted phenyl group or an optionallysubstituted benzyl group; L is a leaving group such as halogen atom, C1to C4 alkylsulfonyl group, optionally substituted phenylsulfonyl group,optionally substituted benzylsulfonyl group or the like; and x is aninteger of 1 or more.

The above production process is described below in detail on each step.

(Step 1)

A sulfide derivative represented by the general formula [5] can beproduced by reacting a compound represented by the general formula [1]with a sodium hydrosulfide hydrate represented by the general formula[2] in the presence or absence of a solvent (preferably in anappropriate solvent) in the presence of a salt to produce a base of amercaptan, represented by the general formula [3] in the reactionsystem, and then, without isolating the salt of a mercaptan [3],reacting the salt [3] with a halogen derivative represented by thegeneral formula [4] [in this case, a radical-generating agent, forexample, Rongalit (trade name): CH₂(OH)SO₂Na.2H₂O may be added].

The reaction temperature in each reaction is any temperature between 0°C. and the reflux temperature of each reaction system and is preferably10 to 100° C. The reaction time varies depending upon the compoundsused, but is 0.5 to 24 hours.

With respect to the amounts of the reagents used in each reaction, eachof the compound represented by the general formula [2] and the compoundrepresented by the general formula [4] is used in an amount of 1 to 3equivalents relative to one equivalent of the compound represented bythe general formula [1] and, when a base is used, the base is used in anamount of 0.5 to 3 equivalents.

As the solvent, there can be mentioned, for example, ethers such asdioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbonssuch as dichloroethane, carbon tetrachloride, chlorobenzene,dichlorobenzene and the like; amides such as N,N-dimethylacetamide,N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; aromatichydrocarbons such as benzene, toluene, xylene and the like; alcoholssuch as methanol, ethanol, propanol, isopropanol, butanol, tert-butanoland the like; ketones such as acetone, 2-butanone and the like; nitrilessuch as acetonitrile and the like; water; and mixtures thereof.

As the base, there can be mentioned, for example, metal hydrides such assodium hydride and the like; alkali metal amides such as sodium amide,lithium diisopropylamide and the like; organic bases such as pyridine,triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like; alkalimetal hydroxides such as sodium; hydroxide, potassium hydroxide and thelike; alkaline earth metal hydroxides such as calcium hydroxide,magnesium hydroxide and the like; alkali metal carbonates such as sodiumcarbonate, potassium carbonate and the like; alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like; and metal alcholates such as sodiummethoxide, potassium tertbutoxide and the like.

(Step 2)

A sulfoxide derivative represented by the general formula [6] can beproduced by reacting the sulfide derivative represented by the generalformula [5] with an oxidizing agent in an appropriate solvent.

The reaction temperature is any temperature between 0° C. and the refluxtemperature of the reaction system and is preferably 0 to 60° C. Thereaction time varies depending upon the compounds used, but is 1 to 72hours.

With respect to the amounts of the reagents used in the reaction, theoxidizing agent is used in an amount of 1 to 3 equivalents perequivalent of the compound represented by the general formula [5].

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloromethane, chloroform, dichloroethane, carbontetrachloride, chlorobenzene, dichlorobenzene and the like; ethers suchas dioxane, tetrahydrofuran (THF), dimethoxyethane, diethyl ether andthe like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide,N-methyl-2-pyrrolidinone and the like; alcohols such as methanol,ethanol, propanol, isopropanol, butanol, tertbutanol and the like;ketones such as acetone, 2-butanone and the like; nitrites such asacetonitrile and the like; acetic acid; water; and mixtures thereof.

As the oxidizing agent, there can be mentioned, for example, organicperoxides such as m-chloroperbenzoic acid, performic acid, peraceticacid and the like; and inorganic peroxides such as hydrogen peroxide,potassium permanganate, sodium periodate and the like.

(Step 3)

A sulfone derivative represented by the general formula [7] can beproduced by reacting the sulfoxide derivative represented by the generalformula [6] with an oxidizing agent in an appropriate solvent.

The reaction temperature is any temperature between 0° C. and the refluxtemperature of the reaction system and is preferably 0 to 60° C. Thereaction time varies depending upon the compounds used, but is 1 to 72hours.

With respect to the amounts of the reagents used in the reaction, theoxidizing agent is used in an amount of 1 to 3 equivalents perequivalent of the compound represented by the general formula [6].

As the solvent and the oxidizing agent, there can be mentioned the samesolvents and oxidizing agents as in the step 2.

(Step 4)

The sulfone derivative represented by the general formula [7] can alsobe produced by reacting the sulfide derivative represented by thegeneral formula [5] with an oxidizing agent of appropriate amount in anappropriate solvent without isolating the sulfoxide derivativerepresented by the general formula [6].

The reaction temperature is any temperature between 0° C. and the refluxtemperature of the reaction system and is preferably 0 to 60° C. Thereaction time varies depending upon the compounds used, but is 1 to 72hours.

With respect to the amounts of the reagents used in the reaction, theoxidizing agent is used in an amount of 1 to 3 equivalents perequivalent of the compound represented by the general formula [5].

As the solvent and the oxidizing agent, there can be mentioned the samesolvents and oxidizing agents as in the step 2.

(Step 5)

The sulfide derivative represented by the general formula [5] can alsobe produced by reacting a compound represented by the general formula[8] with a mercaptan derivative represented by the general formula [9]in the presence or absence of a solvent (preferably in an appropriatesolvent) in the presence of a base.

The reaction temperature is any temperature between 0° C. and the refluxtemperature of the reaction system and is preferably 10 to 100° C. Thereaction time varies depending upon the compounds used, but is 0.5 to 24hours.

With respect to the amounts of the reagents used in the reaction, thecompound represented by the general formula [9] is used in an amount of1 to 3 equivalents per-equivalent of the compound represented by thegeneral formula [8], and the base is used in an amount of 0.5 to 3equivalents.

As the solvent, there can be mentioned, for example, ethers such asdiethyl ether, dimethoxyethane, dioxane, tetrahydrofuran (THF) and thelike; halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene andthe like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide,N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethylsulfoxide, sulfolane and the like; aromatic hydrocarbons such asbenzene, toluene, xylene and the like; alcohols such as methanol,ethanol, propanol, isopropanol, butanol, tert-butanol-and the like;ketones such as acetone, 2-butanone and the like; nitriles such asacetonitrile and the like; water; and mixtures thereof.

As the base, there can be mentioned, for example, metal hydrides such assodium hydride and the like; alkali metal amides such as sodium amide,lithium diisopropylamide and the like; organic bases such as, pyridine,triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like; alkalimetal hydroxides such as sodium hydroxide, potassium hydroxide and thelike; alkaline earth metal hydroxides such as calcium hydroxide,magnesium hydroxide and the like; alkali metal carbonates such as sodiumcarbonate, potassium carbonate and the like; alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like; and metal alcholates such as sodiummethoxide, potassium tertbutoxide and the like.

A compound of the general formula [8] wherein L is a halogen atom, i.e.a compound [12] can be produced by a process shown by the following step6. As necessary, a mixture of the compound [12] and a compound [13] issubjected to a separation and purification procedure to isolate thecompound [12].

In the above reaction, X¹, R¹, R², R³ and R⁴ have the same definitionsas given above.

The isoxazoline compounds represented by the general formulas [12] and[13] can be produced by reacting an olefin derivative represented by thegeneral formula [10] with an oxime derivative represented by the generalformula [11] in the presence or absence of a solvent (preferably in anappropriate solvent) in the presence of a base. When R³ and R⁴ are eacha hydrogen atom, the isoxazoline compound represented by the generalformula [12] can be obtained preferentially.

The reaction temperature is any temperature between 0° C. and the refluxtemperature of the reaction system and is preferably 10 to 80° C. Thereaction time varies depending upon the compounds used, but is 0.5 hoursto 2 weeks.

With respect to the amounts of the reagents used in the reaction, thecompound represented by the general formula [10] is used in an amount of1 to 3 equivalents per equivalent of the compound represented by thegeneral formula [11].

As the solvent, there can be mentioned, for example, ethers such asethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylether, dioxane, tetrahydrofuran and the like; halogenated hydrocarbonssuch as dichloroethane, carbon tetrachloride, chlorobenzene,dichlorobenzene and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; acetic acid esters such as ethyl acetate,butyl acetate and the like; water; and mixtures thereof.

As the base, there can be mentioned, for example, alkali metalhydroxides such as sodium hydroxide, potassium hydroxide and the like;alkaline earth metal hydroxides such as calcium hydroxide, magnesiumhydroxide and the like; alkali metal carbonates such as sodiumcarbonate, potassium carbonate and the like; alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like; alkali metal acetates such as sodiumacetate, potassium acetate and the like; alkali metal fluorides such assodium fluoride, potassium fluoride and the like; and organic bases suchas pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and thelike.

In the above production process, the compound represented by the generalformula [10], used as an intermediate can be a commercial product or canbe produced by a known reaction such as Wittig reaction or the like. Thecompound represented by the general formula [11] can be produced, forexample, by a process described in Liebigs Annalen der Chemie, 985(1989).

The compound represented by the general formula [1] can be produced fromthe above-shown compound represented by the general formula [12] by thefollowing process.

In the above reaction, X¹, R¹, R², R³, R⁴ and R⁷ have the samedefinitions as given above.

A compound represented by the general formula [15] can be produced bythe above-described step 5; a compound represented by the generalformula [16] can be produced by the above-described step 2; and thecompound represented by the general formula [1] can be produced from thecompound [15] by the above-described step 4 or from the compound [16] bythe above-described step 3.

As the solvent, base and oxidizing agent, there can be mentioned thesame solvents, bases and oxidizing agents as mentioned in the step 2, 3,4 or 5.

A compound represented by the general formula [4] wherein R⁶ is ahydrogen atom, i.e. a compound represented by the general formula [21]can be produced by the following process.

In the above reaction, R⁵, X¹ and Y have the same definitions as givenabove; and R⁸ is an alkyl group.

(Step 11)

A compound represented by the general formula [20] can be produced byreacting a compound [17], [18] or [19] with a reducing agent in asolvent.

This reaction is conducted ordinarily at −60 to 150° C. for 10 minutesto 24 hours.

With respect to the amounts of the reagents used in the reaction, thereducing agent is used in an amount of desirably 0.5 to 2 equivalentsper equivalent of the compound [17], [18] or [19]; however, the amountcan be varied appropriately depending upon the condition of thereaction.

As the reducing agent, there can be mentioned, for example, metalhydrides (e.g. diisobutyl aluminum hydride) and metal hydrogen complexcompounds (e.g. sodium borohydride and lithium aluminum hydride) inproduction of [20] from [17]; and metal hydrides (e.g. diisobutylaluminum hydride), metal hydrogen complex compounds (e.g. sodiumborohydride and lithium aluminum hydride) and diborane in production of[20] from [18] or [19].

As the solvent, there can be mentioned, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane and the like; aromatichydrocarbons such as benzene, toluene and the like; and alcohols such asmethanol, ethanol and the like.

(Step 12)

A compound represented by the general formula [21] can be produced byreacting the compound [20] with a halogenating agent in a solvent.

This reaction is conducted ordinarily at −50 to 100° C. for 10 minutesto 24, hours.

With respect to the amounts of the reagents used in the reaction, thehalogenating agent is used in an amount of desirably 1 to 3 equivalentsper equivalent of the compound [20]; however, the amount can be variedappropriately depending upon the condition of the reaction.

As the halogenating agent, there can be mentioned, for example, hydrogenchloride, hydrogen bromide, phosphorus trichloride, phosphorustribromide and thionyl chloride.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride and the like;acids such as acetic acid and the like; and ethers such astetrahydrofuran and the like.

The compound represented by the general formula [4] can be produced bythe following process.

In the above reaction, R⁵, R⁶, X¹ and Y have the same definitions asgiven above.

The compound represented by the general formula [4] can be produced byreacting a compound [22] with a halogenating agent in a solvent in thepresence or absence of a catalyst.

This reaction is conducted ordinarily at 30 to 150° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, thehalogenating agent is used in an amount of desirably 1 to 10 equivalentsrelative to one equivalent of the compound [22]; however, the amount ofthe halogenating agent can be varied appropriately depending upon thecondition of the reaction. The catalyst is used in an amount of 0.01 to0.5 equivalent.

As the halogenating agent, there can be mentioned, for example, halogenssuch as bromine, chlorine and the like; N-halosuccinimides such asN-bromosuccinimide and the like; and pyridine salts such as pyridiniumperbromide and the like.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride,chlorobenzene, dichlorobenzene and the like; amides such asN,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinoneand the like; sulfur compounds such as dimethyl sulfoxide, sulfolane andthe like; and carboxylic acids such as formic acid, acetic acid and thelike.

As the catalyst, there can be mentioned, for example, benzoyl peroxide,α, α-azobisisobutyronitrile and a mixture thereof.

A compound represented by the general formula [4] wherein R⁵ and R⁶ areeach a hydrogen atom, i.e. a compound represented by the general formula[24] can be produced by the following process.

In the above reaction, X¹ and Y have the same definitions as givenabove.

The compound represented by the general formula [24] can be produced byreacting a compound [23], hydrogen halide, and formaldehyde orparaformaldehyde in a solvent in the presence or absence of a Lewis acidaccording to the method described in Org. Synth., III, 557 (1955) or J.Am. Chem. Soc., 72, 2216 (1950), or by reacting the compound [23] with ahalogenomethyl ether in a solvent in the presence of a Lewis acidaccording to the method described in J. Am. Chem. Soc., 97, 6155 (1975).

This reaction is conducted ordinarily at −40 to 150° C. for 10 minutesto 24 hours.

With respect to the amounts of the reagents used in the reaction, thehydrogen halide, formaldehyde, paraformaldehyde, Lewis acid orhalogenomethyl ether is used in an amount of desirably 1 to 2equivalents per equivalent of the compound [23]; however, the amount ofthe former can be varied appropriately depending upon the condition ofthe reaction.

As the Lewis acid, there can be mentioned, for example, titaniumtetrachloride, zinc chloride, aluminum chloride and zinc bromide.

As the hydrogen halide, there can be mentioned hydrogen chloride,hydrogen bromide and hydrogen iodide.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride, chloroformand the like; aliphatic hydrocarbons such as hexane, heptane and thelike; ethers such as dioxane, tetrahydrofuran and the like; carboxylicacids such as acetic acid and the like; carbon disulfide; and mixturesthereof.

A compound represented by the general formula [19] wherein R⁵ is ahydrogen atom, i.e. a compound represented by the general formula [25]can be produced by the following process.

In the above reaction, Y has the same definition as given above.

The compound represented by the general formula [25] can be produced byreacting the compound [23] with N,N-dimethylformamide in the presence ofphosphoryl chloride, phosgene or thionyl chloride in the presence orabsence of a solvent according to the Vilsmeier method described in Org.Synth., IV, 831 (1963), or by reacting the compound [23] with adihalogenomethyl ether in a solvent in the presence of a Lewis acid andthen giving rise to hydrolysis according to the method described inChem. Ber., 93, 88 (1960).

This reaction is conducted ordinarily at −40 to 150° C. for 10 minutesto 24 hours.

With respect to the amounts of the reagents used in the reaction, thephosphoryl chloride, phosgene, thionyl chloride, N,N-dimethylformamide,Lewis acid or dihalogenomethyl ether is used in an amount of desirably 1to 2 equivalents per equivalent of the compound [23]; however, theamount of the former can be varied appropriately depending upon thecondition of the reaction.

As the Lewis acid, there can be mentioned, for example, titaniumtetrachloride, tin tetrachloride, zinc chloride, aluminum chloride andzinc bromide.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride, chloroformand the like; aliphatic hydrocarbons such as hexane, heptane and thelike; ethers such as dioxane, tetrahydrofuran and the like; carboxylicacids such as acetic acid and the like; amides such asN,N-dimethylformamide and the like; carbon disulfide; and mixturesthereof.

The compounds represented by the general formulas [17], [18], [19] and[20] can be produced by the following process.

In the above reaction, R⁵, R⁸ and Y have the same definitions as givenabove; and X² is a chlorine atom, a bromine atom or an iodine atom.

The compounds represented by the general formulas [17], [18], [19] and[20] can be produced by reacting a compound [26] with a magnesiumreagent in the presence or absence of a solvent to obtain a compound[27] and then reacting the compound [27] with an electrophilic reagentaccording to the method described in J. Org. Chem., 65, 4618 (2000), orby reacting the compound [26] with n-butyl lithium in a solvent toobtain a compound [28] and then reacting the compound [28] with anelectrophilic reagent according to the method described in Synth.Commun., 24 (2), 253 (1994).

This reaction is conducted ordinarily at −100 to 150° C. for 10 minutesto 24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the magnesium reagent or the lithium reagent is desirably 1to5 equivalents per equivalent of the compound [26], and the amount of theelectrophilic reagent is desirably 1 to 5 equivalents; however, theseamounts can be varied appropriately depending upon the condition of thereaction.

As the magnesium reagent, there can be mentioned, for example, metalmagnesium, isopropyl magnesium bromide and diisopropyl magnesium.

As the lithium reagent, there can be mentioned, for example, n-butyllithium, sec-butyl lithium and tert-butyl lithium.

As the electrophilic reagent, there can be mentioned, for example,esters such as ethyl formate, ethyl cyanoformate, ethyl acetate and thelike; acid halides such as acetyl chloride, methyl chloroformate and thelike; amides such as N,N-dimethylformamide and the like; aldehydes suchas paraformaldehyde and the like; and carbon dioxide.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride, chloroformand the like; aliphatic hydrocarbons such as hexane, pentane and thelike; ethers such as dioxane, tetrahydrofuran and the like; and mixturesthereof.

Among compounds represented by the general formulas [4], [17], [18],[19], [20], [22], [23], [26], [29] or [34], a compound represented bythe general formula [31] can be produced by the following process.

In the above reaction, Y has the same definition as given above; R⁹ isan alkyl group, a haloalkyl group, a cycloalkyl gorup, a cycloalkylalkylgroup, an alkoxycarbonylalkyl group, an optionally substituted, benzylgroup, an optionally substituted heterocyclic alkyl group, an alkenyltionally substituted heterocyclic alkyl group, an alkenyl group, analkynyl group, an alkylsulfonyl group, a haloalkylsulfonyl group, anoptionally substituted aromatic heterocyclic group, an optionallysubstituted phenylsulfonyl group, an acyl group, a haloalkylcabonylgroup, an optionally substituted benzylcarbonyl group or an optionallysubstituted benzoyl group; and L¹ is a leaving group such as halogenatom, C1 to C4 alkylsulfonate group, C1 to C4 alkylsulfonyl group,optionally substituted benzylsulfonyl group, optionally substitutedphenylsulfonate group, optionally substituted benzylsulfonate group orthe like. When R⁹ is a haloalkyl group, L¹ is a leaving group having ahigher reactivity than the halogen atom remaining after haloalkylation.For example, when R⁹ is a CHF₂ group, L¹ is a chlorine atom or a bromineatom; and when R⁹ is a CH₂CF₃ group, L¹ is a chlorine atom, a bromineatom, a p-toluenesulfonyloxy group or a methylsulfonyloxy group.

The compound represented by the general formula [31] can be produced byreacting a compound [29] with a compound [30] in a solvent in thepresence of a base.

This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the compound [30] is 1 to 20 equivalents per equivalent of thecompound [29], and the amount of the base is 1 to 3 equivalents.

As the base, there can be mentioned, for example, alkali metalcarbonates such as sodium carbonate, potassium carbonate and the like;alkali metal hydroxides such as sodium hydroxide, potassium hydroxideand the like; alkali metal hydrides such as potassium hydride, sodiumhydride and the like; alkali metal alcoholates such as sodium ethoxide,sodium methoxide and the like; and organic bases such as1,8-diazabicyclo[5.4.0]-7-undecene and the like.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloromethane, chloroform and the like; etherssuch as diethyl ether, tetrahydrofuran and the like; aromatichydrocarbons such as benzene, toluene and the like; aliphatichydrocarbons such as hexane, heptane and the like; ketones such asacetone, methyl isobutyl ketone and the like; esters such as ethylacetate, methyl acetate and the like; amides such asN-methylpyrrolidone, N,N-dimethylformamide and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; nitrilessuch as acetonitrile and the like; and mixtures thereof.

Among compounds represented by the general formulas [4], [17], [18],[19], [20], [22], [23], [26], [29] or [31], a compound represented bythe general formula [34] can be produced by the following process,

In the above reaction, L¹ has the same definition as given above; andR¹⁰ is an alkyl group, an alkyl group mono-substituted with a groupselected from the substituent group β, a haloalkyl group, a cycloalkylgroup, an alkenyl group, an alkynyl group, an alkylsulfinyl group, analkylsulfonyl group, an alkylsulfonyl group mono-substituted with agroup selected from the substituent group γ, a haloalkylsulfonyl group,an optionally substituted phenyl group, an optionally substitutedaromatic heterocyclic group, an optionally substituted phenylsulfonylgroup, an optionally substituted aromatic heterocyclicsulfonyl group, anacyl group, a haloalkylcarbonyl group, an optionally substitutedbenzylcarbonyl group, an optionally substituted benzoyl group, analkoxycarbonyl group, an optionally substituted benzyloxycarbonyl group,an optionally substituted phenoxycarbonyl group, or a carbamoyl group(its nitrogen atom may be substituted with same or different groupsselected from alkyl groups and optionally substituted phenyl group). Thecarbon atoms of the pyrazole ring may be substituted with 1 to 2 same ordifferent groups selected from the substituent group α.

The compound represented by the general formula [34] can be produced byreacting a compound [32] with a compound [33] in a solvent in thepresence of a base.

This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the compound [33] is 1 to 20 equivalents per equivalent of thecompound [32], and the amount of the base is 1 to 3 equivalents.

As the base and the solvent, there can be mentioned, for example, thesame bases and solvents as mentioned in production of the compound [31]from the compound [29].

Introduction of a trifluoromethyl group into Y can be conductedaccording to or based on, for example, the methods described in J. Chem.Soc. Perkin Trans. 1, 8, 2293-2299 (1990); J. Fluorine Chem., 50 (3),411-426 (1990); J. Chem. Soc. Chem. Commun., 18, 1389-1391 (1993); J.Chem. Soc. Chem. Commun., 1, 53-54 (1992); Chem. Lett., 1719-1720(1981); Chem. Pharm. Bull., 38 (9), 2446-2458 (1990); J. Chem. Soc.Perkin Trans. 1, 921-926 (1988); Heterocycles, 37 (2), 775-782 (1994);Tetrahedron Lett., 30 (16), 2133-2136 (1989); J. Chem. Soc. PerkinTrans. 1, 2755-2761 (1980); Hetrocycles, 22 (1), 117-124 (1984); Eur. J.Med. Chem. Chim. Ther., 24, 249-258 (1989); Acta Chem. Scand. Ser. B, 38(6), 505-508 (1984); J. Fluorine Chem., 21, 495-514 (1982); J. Chem.Soc. Chem. Commun., 10, 638-639 (1988); J. Fluorine Chem., 67 (1), 5-6(1994); J. Heterocycl. Chem., 31 (6), 1413-1416 (1994); Chem.Heterocycl. Compd., 30 (5), 576-578 (1994); J. Fluorine Chem., 78 (2),177-182 (1996); J. Heterocycl. Chem., 34 (2), 551-556 (1997);Tetrahedron, 55 (52), 15067-15070 (1999); and Synthesis, 11, 932-933(1980).

The compounds represented by the general formulas [4], [17], [18], [19],[20], [21], [22], [23], [24], [25], [26], [29] and [31] can be producedaccording to or based on, for example, the methods described in Methodender Organischen Chemie, E6a, 16-185 (1994) when Y is a furyl group;Methoden der Organischen Chemie, E6a, 186-555 (1994) when Y is a thienylgroup; Methoden der Organischen Chemie, E6a, 556-798 (1994) when Y is apyrrolyl group; Methoden der Organischen Chemie, E8b, 399-763 (1994) andJP-A-2000-219679 when Y is a pyrazolyl group; Methoden der OrganischenChemie, E8a, 45-225 (1993) when Y is an isoxazolyl group; Methoden derOrganischen Chemie, E8a, 668-798 (1993) when Y is an isothiazolyl group;Methoden der Organischen Chemie, E8a, 891-1019 (1993) when Y is anoxazolyl group; Methoden der Organischen Chemie, E8b, 1-398 (1994) whenY is a thiazolyl group; Methoden der Organischen Chemie, E8c, 1-215(1994) when Y is an imidazolyl group; Methoden der Organischen Chemie,E7a, 286-686 (1992) when Y is a pyridyl group; Methoden der OrganischenChemie, E9a, 557-682 (1997) when Y is a pyridazinyl group; Methoden derOrganischen Chemie, E9b/1, 1-249 (1998) when Y is a pyrimidinyl group;Methoden der Organischen Chemie, E9b/1, 250-372 (1998) when Y is apyrazinyl group; Methoden der Organischen Chemie, E9c, 530-796 (1998)when Y is a triazinyl group; Methoden der Organischen Chemie, E8d,305-405 and 479-598 (1994) when Y is a triazolyl group; Methoden derOrganischen Chemie, E8c, 397-818 (1994) when Y is an oxadiazolyl group;Methoden der Organischeh Chemie, E8d, 59-304 (1994) when Y is athiadiazolyl group; Methoden der Organischen Chemie, E6b1, 33-216 (1994)and Published International Patent Application WO-1997/29105 when Y is abenzofuryl group; Methoden der Organischen Chemie, E6b1, 217-322 (1994)when Y is a benzothienyl group; Methoden der Organischen Chemie,E6b1,546-848 (1994), Methoden der Organischen Chemie, E6b2, 849-1336(1994) and Published International Patent Application WO-1997/42188-A1when Y is an indolyl group; Methoden der Organischen Chemie, E8a,1020-1194 (1993) when Y is a benzoxazolyl group; Methoden derOrganischen Chemie, E8b, 865-1062 (1994) when Y is a benzothiazolylgroup; Methoden der Organischen Chemie, E8c, 216-391 (1994) when Y is abenzimidazolyl group; Methoden der Organischen Chemie, E8a, 226-348(1993) when Y is a benzisoxazolyl group; Methoden der OrganischenChemie, E8a, 799-852 (1993) when Y is a benzisothiazolyl group; Methodender Organischen Chemie, E8b, 764-864 (1994) when Y is an indazolylgroup; Methoden der Organischen Chemie, E7a, 290-570 (1991) when Y is aquinolyl group; Methoden der Organischen Chemie, E7a, 571-758 (1991)when Y is an isoquinolyl group; Methoden der Organischen Chemie, E9a,744-789 (1997) when Y is a phthalazinyl group; Methoden der OrganischenChemie, E9b/2, 93-265 (1998) when Y is a quinoxalinyl group; Methodender Organischen Chemie, E9b/2, 1-192 (1998) when Y is a quinazolinylgroup; Methoden der Organischen Chemie, E9a, 683-743 (1997) when Y is acinnolinyl group; and Methoden der Organischen Chemie, E8d, 406-478(1994) when Y is a benzotriazolyl group.

<Production Process 2>

In the above reaction, R¹, R², R³, R⁴, R⁵ and R⁶ have the samedefinitions as given above. The carbon atoms of the pyrazole ring may besubstituted with 1 to 2 same or different groups selected from thesubstituent group α.

A compound of the present invention represented by the general formula[36] can be produced by reacting a compound [35] of the presentinvention, produced by the Production Process 1, with an acid in asolvent.

This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the acid is 1 to 10 equivalents per equivalent of the compound[35]; however, the amount can be varied appropriately depending upon thecondition of the reaction.

As the acid, there can be mentioned, for example, hydrochloric acid,hydrobromic acid and trifluoroacetic acid.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride,chlorobenzene, dichlorobenzene and the like; amides such asN,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinoneand the like; sulfur compounds such as dimethyl sulfoxide, sulfolane andthe like; carboxylic acids such as formic acid, acetic acid and thelike; and water.

<Production Process 3>

In the above reaction, n, L¹, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁰ have thesame definitions as given above. The carbon atoms of the pyrazole ringmay be substituted with 1 to 2 same or different groups selected fromthe substituent group α.

A compound of the present invention represented by the general formula[37] can be produced by reacting the compound [36] of the presentinvention with the compound [33] in a solvent in the presence of a base.

With respect to the amounts of the reagents used in the reaction, theamount of the compound [33] is 1 to 3 equivalents per equivalent of thecompound represented by the general formula [36] and the amount of thebase is 1 to 3 equivalents.

As the solvent, there can be mentioned, for example, ethers such asdioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbonssuch as dichloroethane, carbon tetrachloride, chlorobenzene,dichlorobenzene and the like; amides such as N,N-dimethylacetamide,N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; aromatichydrocarbons such as benzene, toluene, xylene and the like; alcoholssuch as methanol, ethanol propanol, isopropanol, butanol, tert-butanoland the like; ketones such as acetone, 2-butanone and the like; nitritessuch as acetonitrile and the like; water; and mixtures thereof.

As the base, there can be mentioned, for example, metal hydrides such assodium hydride and the like; alkali metal amides such as sodium amide,lithium diisopropylamide and the like; organic bases such as pyridine,triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like; alkalimetal hydroxides such as sodium hydroxide, potassium hydroxide and thelike; alkaline earth metal hydroxides such as calcium hydroxide,magnesium hydroxide and the like; alkali metal carbonates such as sodiumcarbonate, potassium carbonate and the like; alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like; and metal alcoholates such as sodiummethoxide, potassium tert-butoxide and the like.

<Production Process 4>

In the above reaction, R¹, R², R³, R⁴, R⁵ and R⁶ have the samedefinitions as given above; R¹¹ is a hydrogen atom or substituent groupα as mentioned above; X³ is a chlorine atom, a fluorine atom, analkylsulfonyl group or an optionally substituted benzylsulfonyl group;R¹² is an alkyl group, a haloalkyl group, a cycloalkyl group, acycloalkylalkyl group, an alkenyl group, an alkynyl group, an optionallysubstituted phenyl group, an optionally substituted aromaticheterocyclic group, an alkoxycarbonylalkyl group, an optionallysubstituted heterocyclic alkyl group or an optionally substituted benzylgroup; R¹³ is an alkyl group, a haloalkyl group, an optionallysubstituted phenyl group, an optionally substituted aromaticheterocyclic group, an alkoxycarbonylalkyl group or an optionallysubstituted benzyl group; R¹⁴ and R¹⁵ may be the same or different andare each a hydrogen atom, an alkyl group, an optionally substitutedphenyl group; an acyl group, a haloalkylcarbonyl group, an optionallysubstituted benzylcarbonyl group, an optionally substituted benzoylgroup, an alkylsulfonyl group, a haloalkylsulfonyl group, an optionallysubstituted benzylsulfonyl group or an optionally substitutedphenylsulfonyl group; and Z is an oxygen atom, a sulfur atom,N═CR^(11a), CR^(11a)═N, CR^(11a)═CR^(11b) or N—R¹⁶ (wherein R¹⁶ is ahydrogen atom or has the same definition as R¹⁰, and R^(11a) and R^(11b)have the same definition as R¹¹.).

Compounds of the present invention represented by the general formulas[40], [42] and [44] can be produced by reacting a compound of thepresent invention represented by the general formula [38] with acompound [39], a compound [41] and a compound [43], respectively, in thepresence or absence of a solvent and, as necessary, in the presence of abase.

This reaction is conducted ordinarily at 20 to 200° C., preferably 30 to180° C. for 10 minutes to 48 hours and, as necessary, under pressure.

With respect to the amounts of the reagents used in the reaction, theamount of the compound [39], the compound [41] or the compound [43] is 1to 20 equivalents per equivalent of the compound [38].

As the base used as necessary, there can be mentioned, for example,alkali metal hydroxides such as potassium hydroxide, sodium hydroxideand the like; alkali metal hydrides such as potassium hydride, sodiumhydride and the like; alkali metal alcoholates such as sodium ethoxide,sodium methoxide and the like; and organic bases such as1,8-diazabicyclo[5.4.0]-7-undecene and the like.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as chloroform and the like; ethers such as diethylether, tetrahydrofuran and the like; aromatic hydrocarbons such asbenzene, toluene and the like; aliphatic hydrocarbons such as hexane,heptane and the like; ketones such as acetone, methyl isobutyl ketoneand the like; esters such as ethyl acetate and the like; amides such asN-methylpyrrolidone, N,N-dimethylformamide and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like;acetonitrile; and mixtures thereof.

<Production Process 5>

In the above reaction, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R¹¹ and Z have thesame definitions as given above.

A compound of the present invention represented by the general formula[46] can be produced by reacting a compound [45] of the presentinvention with an acid in a solvent.

This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the acid is desirably 1 to 10 equivalents per equivalent ofthe compound [45]; however, the amount can be varied appropriatelydepending upon the condition of the reaction.

As the acid and the solvent, there can be mentioned the same acids andsolvents as mentioned in the Production Process 2.

<Production Process 6>

In the above reaction, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁹ and L¹ have thesame definitions as given above. Y may be substituted with 1 to 5 sameor different groups selected from the substituent group α.

A compound represented by the general formula [48] according to thepresent invention can be produced by reacting a compound [47] of thepresent invention with the compound [30] in a solvent in the presence ofa base.

This reaction is conducted ordinarily at 0 to 150° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the acid is desirably 1 to 1.2 equivalents per equivalent ofthe compound [47]; however, the amount can be varied appropriatelydepending upon the condition of the reaction.

As the base and the solvent, there can be mentioned the same bases andsolvents as mentioned in the Production Process 3.

<Production Process 7>

In the above reaction, Y, R¹, R², R³, R⁴, R⁵ and R⁶ have the samedefinitions as given above; and R¹⁷ is an alkyl group, an optionallysubstituted benzyl group or an optionally substituted phenyl group. Ymay be substituted with 1 to 5 same or different groups selected fromthe substituent group α.

A compound represented by the general formula [50] according to thepresent invention can be produced by hydrolyzing a compound [49] of thepresent invention in water or a mixed solvent of water and other solventin the presence or absence of a base.

This reaction is conducted ordinarily at 0 to 100° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the base, when used, is desirably 1 to 2 equivalents perequivalent of the compound [49]; however, the amount can be variedappropriately depending upon the condition of the reaction.

As the base, there can be mentioned, for example, inorganic bases suchas potassium carbonate, sodium hydride, sodium hydroxide and the like;and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene and thelike.

As the other solvent mixed with water, there can be mentioned, forexample, alcohols such as methanol, ethanol and the like; ethers such astetrahydrofuran and the like; ketones such as acetone, methyl isobutylketone and the like; amides such as N,N-dimethylformamide and the like;sulfur compounds such as dimethyl sulfoxide, sulfolane and the like;acetonitrile; and mixtures thereof.

<Production Process 8>

In the above reaction, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R⁸ have the samedefinitions as given above; and R¹⁸ is an alkyl group. Y may besubstituted with 1 to 5 same or different groups selected from thesubstituent group α.

A compound represented by the general formula [53] according to thepresent invention can be produced by reacting a compound [51] of thepresent invention with a compound [52] in a solvent in the presence of abase.

This reaction is conducted ordinarily at 0 to 100° C. for 10minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the hydrochloride or sulfate of the compound [52] is desirably1 to 5 equivalents per equivalent of the compound [51] and the amount ofthe base is desirably 1 to 10 equivalents; however, these amounts can bevaried, appropriately depending upon the condition of the reaction.

As the base, there can be mentioned, for example, metal carbonates suchas potassium carbonate, sodium carbonate and the like; metal acetatessuch as potassium acetate, sodium acetate and the like; and organicbases such as triethylamine, dimethylamine,1,8-diazabicyclo[5.4.0]-7-undecene and the like.

As the solvent, there can be mentioned, for example, alcohols such asmethanol, ethanol and the like; ethers such as tetrahydrofuran and thelike; amides such as N,N-dimethylformamide and the like; water; andmixtures thereof.

<Production Process 9>

In the above reaction, Y, R¹, R², R³, R⁴, R⁵ and R⁶ have the samedefinitions as given above; and R¹⁹ and R²⁰ are each a hydrogen atom oran alkyl group. Y may be substituted with 1 to 5 same or differentgroups selected from the substituent group α.

A compound represented by the general formula [57] according to thepresent invention can be produced by reacting the compound [50] of thepresent invention with thionyl chloride in the presence or absence of asolvent to obtain a compound [55] and then reacting the compound [55]with a compound [56] in the presence or absence of a solvent.

The reaction from the compound [50] to the compound [55] is conductedordinarily at 0 to 100° C. for 10 minutes to 24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of thionyl chloride [54] is desirably 1 to 100 equivalents perequivalent of the compound [50] but it can be varied appropriatelydepending upon the condition of the reaction.

As the solvent, there can be mentioned, for example, halogenatedhydrocarbons such as dichloromethane, chloroform and the like; etherssuch as diethyl ether, tetrahydrofuran and the like; and aromatichydrocarbons such as benzene, toluene and the like.

The reaction from the compound [55] to the compound [57] is conductedordinarily at 0 to 100° C. for 10 minutes to 24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the compound [56] is desirably 1 to 100 equivalents perequivalent of the compound [55] but it can be varied appropriatelydepending upon the condition of the reaction.

As the solvent, there can be mentioned, for example, the same solventsas used in the reaction from the compound [50] to the compound [55].

<Production Process 10>

In the above reaction, Z, R¹, R², R³, R⁴, R⁵, R⁶, R¹¹ and X³ have thesame definitions as given above.

A compound represented by the general formula [59] according to thepresent invention can be produced by reacting the compound [38] of thepresent invention with a compound [58] in a solvent.

This reaction is conducted ordinarily at 0 to 100° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the compound [58] is desirably 1 to 2 equivalents perequivalent of the compound [38] but it can be varied appropriatelydepending upon the condition of the reaction.

As the solvent, there can be mentioned, for example, ethers such asdioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbonssuch as dichloroethane, carbon tetrachloride, chlorobenzene,dichlorobenzene and the like; amides such as N,N-dimethylacetamide,N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; ketonessuch as acetone, 2-butanone and the like; nitriles such as acetonitrileand the like; water; and mixtures thereof.

<Production Process 11>

In the above reaction, Y, R¹, R², R³, R⁴, R⁵ and R⁶ have the samedefinitions as given above; and R²¹ is an alkyl group, a haloalkylgroup, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, analkynyl group, an alkoxycarbonylalkyl group, an optionally substitutedheteroalkyl group or an optionally substituted benzyl group. Y may besubstituted with 1 to 5 same or different groups selected from thesubstituent group α.

A compound represented by the general formula [61] according to thepresent invention can be produced by reacting the compound [47] of thepresent invention with a compound [60] in the presence of an azocompound and triphenylphosphine in a solvent according to a known method[Synthesis, 1-28 (1981)].

This reaction is conducted ordinarily at 0 to 100° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamounts of the compound [60], the azo compound and triphenylphosphineare desirably each 1 to 1.5 equivalents per equivalent of the compound[47] but the amounts can be varied appropriately depending upon thecondition of the reaction.

As the solvent, there can be mentioned, for example, ethers such asdioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbonssuch as dichloroethane, carbon tetrachloride, chlorobenzene,dichlorobenzene and the like; amides such as N,N-dimethylacetamide,N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; aromatichydrocarbons such as benzene, toluene, xylene and the like;acetonitrile; and mixtures thereof.

As the azo compound, there can be mentioned, for example, diethylazodicarboxylate and diisopropyl azodicarboxylate.

<Production Process 12>

In the above reaction, X³, n, R¹, R², R³, R⁴, R⁵, R⁶ and Z have the samedefinitions as given above; and m is an integer of 1 to 4. The carbonatom of the 3-position of the pyrazole ring may be substituted with agroup selected from the substituent group α.

A compound represented by the general formula [63] according to thepresent invention can be produced by reacting a compound [62] of thepresent invention in the presence of a base in a solvent.

This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to24 hours.

With respect to the amounts of the reagents used in the reaction, theamount of the base is desirably 1 to 3 equivalents per equivalent of thecompound represented by the general formula [62] but the amount can bevaried appropriately depending upon the condition of the reaction.

As the base and the solvent, there can be mentioned the same bases andsolvents as mentioned in the Production Process 3.

Incidentally, the sulfide compound mentioned in the Production Process 2or the Production Processes 4 to 11 can be converted into a sulfoxidecompound or a sulfone compound by oxidation according to the methoddescribed in the Production Process 1. Furthermore, the sulfide compoundmentioned in the Production Process 2 or the Production Processes 4 to11 wherein substituent Y is substituted by C1 to C10 alkylthio group, C1to C10 alkylthio group mono-substituted with a group selected from thesubstituent group γ or C1 to C4 haloalkylthio group, can be convertedinto a sulfoxide compound or a sulfone compound according to the methoddescribed in the Production Process 1, by adding equi-molar to excessamount of an oxidizing agent to the sulfide compound; oxidizing thesubstituent substituted to substituent Y (C1 to C10 alkylthio group, C1to C10 alkylthio group mono-substituted with a group selected from thesubstituent group γ or C1 to C4 haloalkylthio group) at the same time,and convert these substituent into a sulfoxide group or a sulfone group.

Then, specific description is made on the production process of thepresent compound, the production method of the present herbicide and theapplication of the present herbicide by way of Examples. Description isalso made on the production process of each intermediate of the presentcompound.

EXAMPLE 1 Production of3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0001)

2.1 g of sodium hydrosulfide hydrate (purity: 70%, 26.2 mmoles) wasadded to a solution of 2.3 g (13.1 mmoles) of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 20 ml ofN,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto wereadded 1.8 g (13.1 mmoles) of anhydrous potassium carbonate, 2.0 g (13.1mmoles) of Rongalit and 3.6 g (10.5 mmoles) of4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole. Theresulting mixture was stirred at room temperature for 15 hours to giverise to a reaction. After the completion of the reaction, the reactionmixture was poured into water, followed by extraction with ethylacetate. The resulting organic layer was washed with an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography (developing solvent: hexane-ethyl acetate mixed solvent)to obtain 2.7 g (yield: 65.5%) of3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas white crystals (melting point: 89 to 90° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.55-7.50 (5H, m), 4.33 (2H, s), 2.83 (2H,s), 1.45 (6H, s)

EXAMPLE 2 Production of3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0002)

0.63 g of m-chloroperbenzoic acid (purity: 70%, 2.6 mmoles) was added,with ice-cooling, to a solution of 0.4 g (1.0 mmoles) of3-(5-chloro-1-phenyl-3-trifluoromethyl-1-H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 15 ml of chloroform. The mixture was stirred at roomtemperature for 22 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with chloroform. The resulting organic layer waswashed with an aqueous sodium hydrogensulfite solution, an aqueoussodium hydrogencarbonate solution and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The resulting crystals were washed withhexane to obtain 0.4 g (yield: 83.2%) of3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas white crystals (melting point: 132 to 133° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.60-7.51 (5H, m), 4.37 (2H, s), 3.14 (2H,s) 1.53 (6H, s)

EXAMPLE 3 Production of3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0003)

0.87 g of m-chloroperbenzoic acid (purity: 70%, 3.54 mmoles) was added,with ice-cooling, to a solution of 0.85 g (2.53 mmoles) of3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 30 ml of chloroform. The mixture was stirred at roomtemperature for 1 hour to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water, followed byextraction with chloroform. The resulting organic layer was washed withan aqueous sodium hydrogensulfite solution, an aqueous sodiumhydrogencarbonate solution and an aqueous sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography (developing solvent: hexane-ethyl acetate mixed solvent)to obtain 0.48 g (yield: 53.9%) of3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfinyl)-5,5-dimethyl-2-isoxazolineas a transparent viscous substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.63-7.60 (2H, m), 7.48-7.37 (3H, m), 4.29(2H, q), 3.91 (3H, s), 3.12 (1H, d), 2.79 (1H, d), 1.41 (3H, s), 1.35(3H, s)

EXAMPLE 4 Production of5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound No. 3-0021)

9.3 g of sodium hydrosulfide hydrate (purity: 70%, 116.3 mmoles) wasadded to a solution of 18.7 g (105.7 mmoles) of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline (present compound No. 2-1)dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirredfor 2 hours. The reaction system was ice-cooled. Thereto was added asolution of 30.3 g (93.8 mmoles) of4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole dissolvedin 200 ml of N,N-dimethylformamide. The mixture was stirred at 0° C. for30 minutes to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 13.11 g (yield: 37.4%) of5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolineas a yellow oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.65-7.39 (5H, m), 4.24 (2H, s), 2.81 (2H,s), 1.43 (6H, s)

EXAMPLE 5 Production of5,5-dimethyl-3-(5-ehtylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound No. 3-0022)

0.2 g (4.0 mmoles) of sodium hydroxide and 1 ml of water were added to asolution of 0.25 g (4.0 mmoles) of ethanethiol dissolved in 10 ml ofN,N-dimethylformamide. The mixture was stirred at room temperature for30 minutes. Thereto was added a solution of 0.5 g (1.4 mmoles) of5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 5 ml of N,N-dimethylformamide. The resulting mixture wasstirred for 1 hour to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 0.6 g(yield: 100%) of5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.62-7.47 (5H, m), 4.44 (2H, s), 2.83 (2H,s), 2.50 (2H, q), 1.45 (6H, s), 1.02 (3H, t)

EXAMPLE 6 Production of5,5-dimethyl-3-(5-ethylsulfonyl-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline(present compound No. 3-0004)

1.7 g of m-chloroperbenzoic acid (purity: 70%, 6.7 mmoles) was added,with ice-cooling, to a solution of 0.6 g (1.3 mmoles) of5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 16 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with chloroform. The resulting organic layer waswashed with an aqueous sodium hydrogensulfite solution, an aqueoussodium hydrogencarbonate solution and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The resulting crystals were washed withhexane to obtain 0.6 g (yield: 93.0%) of5,5-dimethyl-3-(5-ethylsulfonyl-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazolineas light yellow crystals (melting point: 158 to 160° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.58-7.54 (5H, m), 5.16 (2H, s), 3.18 (2H,s), 3.15 (2H, q), 1.55 (6H, s), 1.24 (3H, t)

EXAMPLE 7 Production of5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound 3-0023)

0.8 g (6.7 mmoles) of a 40% aqueous dimethylamine solution was added toa solution of 0.5 g (1.3 mmoles) of5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at100° C. for 9 hours in a sealed tube. Thereto was added 3.0 g (26.6mmoles) of a 40% aqueous dimethylamine solution, and the resultingmixture was stirred for 9 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with an aqueous sodium chloride solution and then dried overanhydrous sodium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 0.4 g (yield: 80.6%) of5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.58-7.38 (5H, m), 4.35 (2H, s), 2.82 (2H,s), 2.77 (6H, s), 1.45 (6H, s)

EXAMPLE 8 Production of5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline(present compound 3-0005)

0.7 g of m-chloroperbenzoic acid (purity: 70%, 2.7 mmoles) was added,with ice-cooling, to a solution of 0.4 g (1.1 mmoles) of5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with chloroform. The resulting organic layer waswashed with an aqueous sodium hydrogensulfite solution, an aqueoussodium hydrogencarbonate solution and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The resulting crystals were washed withhexane to obtain 0.2 g (yield: 52.0%) of5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazolineas a white powder (melting point: 150 to 151° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.61-7.38 (5H, m), 4.75 (2H, s), 3.13 (2H,s), 2.76 (6H, s), 1.53 (6H, s)

EXAMPLE 9 Production of3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0006)

21.8 g of sodium hydrosulfide (purity: 70%, 272.5 mmoles) was added to asolution of 24.1 g (136.0 mmoles) of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 200 ml ofN,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto wereadded 18.8 g (136.2 mmoles) of anhydrous potassium carbonate and 21.0 g(136.2 mmoles) of Rongalit. The resulting mixture was stirred for 2hours. Thereto was added, with ice-cooling, 40 g (125 mmoles) of4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole. Theresulting mixture was stirred at room temperature for 2 hours to giverise to a reaction. After the completion of the reaction, the reactionmixture was poured into water, followed by extraction with ethylacetate. The resulting organic layer was washed with water and anaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (developing solvent: hexane-ethyl acetatemixed solvent) to obtain 23.0 g (yield: 57.1%) of3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas light pink crystals (melting point: 79.0 to 81.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.24 (2H, s), 2.80 (2H, s), 1.71 (9H, s),1.43 (6H, s)

EXAMPLE 10 Production of3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0007)

19.8 g (53.4 mmoles) of3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinewas added to 170 ml of a 25% hydrogen bromide-acetic acid solution. Themixture was stirred at 40 to 50° C. for 2 hours to give rise to areaction. After the completion of the reaction was confirmed, thereaction mixture was poured into water, followed by extraction withethyl acetate. The resulting organic layer was washed with water and anaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein, to obtain 12.0 g (yield: 60.6%) of3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas light yellow crystals (melting point: 120.0 to 122.0° C.)

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.26 (2H, s), 2.81 (2H, s), 1.44 (6H, s)

EXAMPLE 11 Production of3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0008) and3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound 3-0009)

3.1 g (22.5 mmoles) of anhydrous potassium carbonate was added to asolution of 2.3 g (7.3 mmoles) of3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 50 ml of N,N-dimethylformamide. Thereinto was blownchlorodifluoromethane. The resulting mixture was stirred at 130 to 140°C. for 3 hours to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was pored into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.69g (yield: 25.8%) of3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas light yellow crystals (melting point: 41.0 to 42.0° C.) and 0.54 g(yield: 20.2%) of3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas a white powder (melting point: 89.0 to 90.0° C.).3-(5-Chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.22 (1H, t), 4.25 (2H, s), 2.80 (2H, s),0.44 (6H, s)3-(3-Chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.19 (1H, t), 4.28 (2H, s), 2.80 (2H, s),1.44 (6H, s)

EXAMPLE 12 Production of3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0010)

1.4 g of m-chloroperbenzoic acid (purity: 70%, 8.1 mmoles) was added,with ice-cooling, to a solution of 0.69 g (1.9 mmoles) of3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. Theresulting solid was washed with n-hexane to obtain 0.4 g (yield: 53.3%)of3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas a white powder (melting point: 126.0 to 127.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.26 (1H, t), 4.68 (2H, s), 3.11 (2H, s),1.53 (6H, s)

EXAMPLE 13 Production of3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0011)

1.1 g of m-chloroperbenzoic acid (purity: 70%, 6.4 mmoles) was added,with ice-cooling, to a solution of 0.54 g (1.5 mmoles) of3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. Theresulting solid was washed, with n-hexane to obtain 0.47 g (yield:79.7%) of3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas a white powder (melting point: 136.0 to 137.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.23 (1H, t), 4.71 (2H, s), 3.11 (2H, s),1.53 (6H, s)

EXAMPLE 14 Production of5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound No. 3-0024)

3.1 g of sodium hydrosulfide hydrate (purity: 70%, 22.0 mmoles) wasadded to a solution of 3.3 g (17.3 mmoles) of5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 10 ml ofN,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto wereadded 3.1 g (22.0 mmoles) of anhydrous potassium carbonate, 2.7 g (17.5mmoles) of Rongalit and 4.0 g (17.5 mmoles) of4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole. Theresulting mixture was stirred at room temperature for 2 hours to giverise to a reaction. After the completion of the reaction, the reactionmixture was poured into water, followed by extraction with ethylacetate. The resulting organic layer was washed with an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography (developing solvent: hexane-ethyl acetate mixed solvent)to obtain 2.8 g (yield: 52.0%) of5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

EXAMPLE 15 Production of5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound No. 3-0025)

To 20 ml of a 25% hydrogen bromide acetic acid solution was added 3.3 g(10.6 mmoles) of5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.The mixture was stirred at 50° C. for 3 hours to give rise to areaction. After the completion of the reaction, the reaction mixture wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was poured into water. The resulting crystals werecollected by filtration, washed with water and dried to obtain 3.1 g(yield: 96.0%) of intended5,5-dimethyl-3-(3-hydroxy-1-methyl-.5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

EXAMPLE 16 Production of5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound No. 3-0026)

0.20 g (1.3 mmoles) of anhydrous potassium carbonate and 0.20 g (1.5mmoles) of ethyl iodide were added to a solution of 0.30 g (1.0 mmoles)of5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at50° C. for 3 hours to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 0.30 g(yield: 92.0%) of intended5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

EXAMPLE 17 Production of5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline(present compound No. 3-0012)

0.68 g of m-chloroperbenzoic acid (purity: 70%, 2.76 mmoles) was added,with ice-cooling, to a solution of 0.30 g (0.92 mmoles) of5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 5 hours to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water, followed byextraction with chloroform. The resulting organic layer was washed withan aqueous sodium hydrogensulfite solution, an aqueous sodiumhydrogencarbonate solution and an aqueous sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The resulting crystals were washed withhexane to obtain 0.24 g (yield: 73.0%) of5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazolineas white crystals (melting point: 124 to 125° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.50 (2H, s), 4.27 (2H, q), 3.86 (3H, s),3.04 (2H, s), 1.49 (6H, s), 1.39 (3H, t)

EXAMPLE 18 Production of5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound No. 3-0027)

19.3 g of sodium hydrosulfide (purity: 70%, 344.6 mmoles) was added to asolution of 21.3 g (120.3 mmoles) of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 200 ml ofN,N-dimethyl-formamide. The mixture was stirred for 1 hour. Thereto wereadded 16.7 g (121.0 mmoles) of anhydrous potassium carbonate and 18.6 g(120.7 mmoles) of Rongalit. The resulting mixture was stirred for 2hours. Thereto was added, with ice-cooling, 31.4 g (120.3 mmoles) of4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole. Theresulting mixture was stirred at room temperature for 2 hours to giverise to a reaction. After confirmation of the completion of thereaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith water and an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove-the solvent contained therein, to obtain29.0 g (yield: 90.3%) of5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylyhio)-2-isoxazolineas a yellow oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.24 (2H, s), 3.90 (3H, s), 2.78 (2H, s),1.42 (6H, s)

EXAMPLE 19 Production of5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline(present compound No. 3-0028)

0.77 g (4.0 mmoles) of sodium methoxide (a 28% methanol solution) wasadded to a solution of 0.5 g (1.6 mmoles) of5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 20 ml of methanol. The mixture was stirred for 4 hoursunder refluxing, to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 0.5 g (yield: 96.7%) of5,5-dimethyl-3-(5-methoxy-2-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolineas a yellow oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.26 (2H, s), 4.07 (3H, s), 3.72 (3H, s),2.80 (2H, s), 1.43 (6H, s)

EXAMPLE 20 Production of5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline(present compound No. 3-0013)

1.3 g of m-chloroperbenzoic acid (purity: 70%, 7.5 mmoles) was added,with ice-cooling, to a solution of 0.5 g (1.5 mmoles) of5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. Theresulting solid was washed with n-hexane to obtain 0.31 g (yield:58.2%). of5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazolineas a white powder (melting point: 113.0 to 114.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.60 (2H, s), 4.11 (3H, s), 3.79 (3H, s),3.10 (2H, s), 1.51 (6H, s)

EXAMPLE 21 Production of3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyraxzol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0029)

0.2 g (8.3 mmoles) of sodium hydride (purity: 60%) was added, withice-cooling, to a solution of 0.44 g (3.4 mmoles) of 2-chlorophenoldissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for1 hour. Thereto was added 0.7 g (2.2 mmoles) of5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolineThe resulting mixture was stirred at 120 to 130° C. for 5 hours to giverise to a reaction. After confirmation of the completion of thereaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith water and an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 0.63 g (yield: 66.7%) of3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyraxzol-4-ylmethylthio)-2-isoxazoline-5,5-dimethyl-2-isoxazolineas a yellow oily substance.

EXAMPLE 22 Production of3-(5-(2-chlorophenoxy)-17-methyl-3trifluoromethyl-1H-pyraxzol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0014)

1.0 g of m-chloroperbenzoic acid (purity: 70%, 5.8 mmoles) was added,with ice-cooling, to a solution of 0.63 g (1.5 mmoles) of3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride: solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. Theresulting solid was washed with n-hexane to obtain 0.31 g (yield: 45.7%)of3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas a white powder (melting point: 67.0 to 70.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.50-6.91 (4H, m), 4.45 (2H, s), 3.71 (3H,s), 3.03 (2H, s), 1.47 (6H, s)

EXAMPLE 23 Production of3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0030)

To a solution of 0.43 g (1.6 mmoles) of triphenylphosphine dissolved in10 ml of benzene were added 0.14 g (1.6 mmoles) of cyclopentanol, 0.5 g(1.6 mmoles) of5,5dimethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolineand 0.7 g (1.6 mmoles) of di-ethyl azodicarboxylate (a 40%, toluenesolution). The mixture was stirred at room temperature for 12 hours togive rise to a reaction. After confirmation of the completion of thereaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith water and an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting organic layer was subjectedto vacuum distillation to remove the solvent contained therein. Theresidue was purified by silica, gel column chromatography (developingsolvent: hexane-ethyl acetate mixed solvent) to obtain 0.52 g (yield:85.2%) of3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas a colorless transparent oily substance.

EXAMPLE 24 Production of3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0015)

0.85 g of m-chloroperbenzoic acid (purity: 70%, 4.9 mmoles) was added,with ice-cooling, to a solution of 0.52 g (1.4 mmoles) of3-(5-(cyclopentyloxy-1-methyl-3trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. Theresulting solid was washed with n-hexane to obtain 0.2 g (yield: 35.5%)of3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas a white powder (melting point: 113.0 to 114.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 5.03 (1H, br), 4.60 (2H, s), 3.73 (3H, s),3.05 (2H, s), 1.88-1.70 (8H, m), 1.50 (6H, s)

EXAMPLE 25 Production of3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0031)

0.2 g (4.0 mmoles) of sodium cyanide was added to a solution of 0.5 g(1.6 mmoles) of5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazolinedissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred at40° C. for 1 hour to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 0.9 g of crude3-(5cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas a yellow oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.30 (2H, s), 4.08 (3H, s), 2.81 (2H, s),1.43 (6H, s)

EXAMPLE 26 Production of3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0016)

2.1 g of m-chloroperbenzoic acid (purity: 70%, 12.2 mmoles) was added,with ice-cooling, to a solution of 0.9 g of3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4ylmethylthio)-5,5-dimethyl-2-isoxazoline(crude compound) dissolved in 50 ml of chloroform. The mixture wasstirred for 1 hour and then-at room temperature for 12 hours to giverise to a reaction. After confirmation of the completion of thereaction, the reaction mixture was poured into water, followed byextraction with chloroform. The resulting organic layer was washed withan aqueous sodium hydrogensulfite solution, an aqueous sodiumhydrogencarbonate solution, water and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The resulting solid was washed withn-hexane to obtain 0.43 g (yield: 76.4%) of3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas a white, powder (melting point: 105.0 to 108.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.73 (2H, s), 4.16 (3H, s), 3.14 (2H, s),1.53 (6H, s)

EXAMPLE 27 Production of3-(3,5-dichloro-1-ethyl-1H-pyrazol-4ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0032)

0.6 g of sodium hydrosulfide (purity: 70%, 10.7 mmoles) was added to asolution of 0.7 g (3.7 mmoles) of5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 30 ml ofN,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto wereadded 0.51 g (3.7 mmoles) of anhydrous potassium carbonate and 0.56 g(3.6 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours.Thereto was added, with ice-cooling, 0.9 g (3.5 mmoles) of4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole. The resulting mixturewas stirred at room temperature for 2 hours to give rise to a reaction.After confirmation of the completion of the reaction, the reactionmixture was poured into water, followed by extraction with ethylacetate. The resulting organic layer was washed with water and anaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (developing solvent: hexane-ethyl acetatemixed solvent) to obtain 0.8 g (yield: 70.8%) of3-(3,5-dichloro-1-ethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas a colorless transparent oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.14 (2H, s), 4.14 (2H, q), 2.81 (2H, s),1.43 (6H, s), 1.42 (3H, t)

EXAMPLE 28 Production of3-(3,5-dichloro-1-ethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0017)

2.0 g of m-chloroperbenzoic acid (purity: 70%, 11.6 mmoles) was added,with ice-cooling, to a solution of 0.8 g (2.6 mmoles) of3-(3,5-dichloro-1-ethyl1H-pyrazol-4ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. Theresulting solid was washed with n-hexane to obtain 0.41 g (yield: 46.6%)of3-(3,5-dichloro-1-ethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas a white powder (melting point: 105.0 to 107.0° C.)

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.48 (2H, s), 4.19 (2H, q), 3.05 (2H, s),1.51 (6H, s), 1.45 (3H, t)

EXAMPLE 29 Production of3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0020)

1.2 g of sodium hydrosulfide hydrate (purity: 70%, 15.0 mmoles) wasadded to a solution of 1.9 g (10.0 mmoles) of5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 30 ml ofN,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto wereadded 2.1 g (15.0 mmoles) of anhydrous potassium carbonate, 2.3 g (15.0mmoles) of Rongalit and 2.6 g (10.0 mmoles) of4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole. Theresulting mixture was stirred at room temperature for 15 hours to give,rise to a reaction. After the completion of the reaction, the reactionmixture was poured into water, followed by extraction with ethylacetate. The resulting organic layer was washed with an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography (developing solvent: hexane-ethyl acetate mixed solvent)to obtain 2.1 g (yield: 68.0%) of3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolineas a colorless viscous liquid (n_(D) ²⁰ =1.5183).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 6.70 (1H, t, J=54.2 Hz), 4.24 (2H, s), 3.86(3H, s) 2.80 (2H, s), 1.42 (6H, s)

EXAMPLE 30 Production of3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline(present compound No. 3-0018)

3.6 g of m-chloroperbenzoic acid (purity:, 70%, 14.5 mmoles) was added,with ice-cooling, to a solution of 1.8 g (5.8 mmoles) of3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved 30 in 15 ml of chloroform. The mixture was stirred at roomtemperature for 22 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with chloroform. The resulting organic layer waswashed with an aqueous sodium hydrogensulfite solution, an aqueoussodium hydrogencarbonate solution and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The resulting crystals were washed withhexane to obtain 1.7 g (yield: 85.9%) of3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazolineas white crystals (melting point: 78 to 79° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 6.80 (1H, t, J=54.8 Hz), 4.60 (2H, s), 3.91(3H, s), 3.08 (2H, s), 1.51 (6H, s)

EXAMPLE 31 Production of5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmethylthio)-2-isoxazoline(present compound No. 4-0003)

0.4 g of sodium hydrosulfide hydrate (purity: 70%, 4.6 mmoles) was addedto a solution of 0.4 g (2.3 mmoles) of5,5-dimethyl-3-methylsulfonyl-2-isoxazline dissolved in 10 ml ofN,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto wereadded 0.3 g (2.3 mmoles) of potassium carbonate, 0.4 g (2.3 mmoles) ofRongalit and 0.5 g (1.8 mmoles) of4bromomethyl-5-methyl-3-trifluoromethylisoxazole. The resulting mixturewas stirred at room temperature for 14 hours to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water, followed by extraction with ethyl acetate. The resultingorganic layer was washed with an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g(yield: 70.0%) of5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmethylthio)-2-isoxazoline.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.11 (2H, s), 2.77 (2H, s), 2.54 (3H, s),1.42 (6H, s)

EXAMPLE 32 Production of5,5-dimethyl-3-(5-methyl-3trifluoromethylisoxazol-4-ylmehtylsulfonyl)-2-isoxazoline(present compound No. 4-0001)

0.8 g of m-chloroperbenzoic acid (purity: 70%, 3.2 mmoles) was added,with ice-cooling, to a solution of 0.4 g (1.3 mmoles) of5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmehtylthio)-2-isoxazolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 4 hours to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water, followed byextraction with chloroform. The resulting organic layer was washed withan aqueous sodium hydrogensulfite solution, an aqueous sodiumhydrogencarbonate solution and an aqueous-sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The resulting crystals were washed withhexane to obtain 0.4 g (yield: 95.0%) of5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmehtylsulfonyl)-2-isoxazolineas white crystals (melting point: 135 to 136° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.54 (2H, s), 3.11 (2H, s), 2.61 (3H, s),1.52 (6H, s)

EXAMPLE 33 Production of[(5-chloro-3-methyl-isothiazol-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline(present compound No. 4-0004)

0.82 g of sodium hydrosulfide (purity: 70%, 10.00 mmoles) was added atthe room temperature to a solution of 0.89 g (5.00 mmoles) of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 10 ml ofN,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto wereadded 0.70 g (5.00 mmoles) of anhydrous potassium carbonate, 0.78 g(5.00 mmoles) of Rongalit and 0.91 g (5.00 mmoles) of5-chloro-4-chloromethyl-3-methylisothiazole. The resulting mixture wasstirred at room temperature overnight to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with ethyl acetate. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography to obtain 1.38 g (yield: quantitative) of[(5-chloro-3-methyl-isothiazol-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline.

EXAMPLE 34 Production of[(5-chloro-3-methyl-isothiazol-4-yl)-methylsulfonyl]-5,5-dimethyl-2-isoxazoline(present compound No. 4-0002)

2.96 g of m-chloroperbenzoic acid (purity: 70%, 12.00 mmoles) was added,with ice-cooling, to a solution of 1.38 g (5.00 mmoles) of[(5-chloro-3-methyl-isothiazol-4-yl)-methylthio]-5,5-dimethyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for overnight to give rise to a reaction. Afterthe completion of the reaction, the reaction mixture was poured intowater, followed by extraction with chloroform. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, anaqueous sodium hydrogencarbonate solution and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The reside was purified by silica gelcolumn chromatography to obtain 0.65 g (yield: 47.0%) of[(5-chloro-3-methyl-isothiazol-4-yl)-methylsulfonyl]-5,5-dimethyl-2-isoxazolineas a light yellow powder (melting point: 113 to 114° C.)

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.89 (1H, s), 4.67 (2H, s), 3.05 (2H, s),2.59 (3H, s) 1.51 (6H, s)

EXAMPLE 35 Production of5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylthio]-2-isoxazoline(present compound No. 2-0002)

0.57 g (6.8 mmoles) of O-methylhydroxylamine hydrochloride and 0.56 g(6.8 mmoles) of sodium acetate were added to a solution of 1.0 g (3.4mmoles) of3-(4-acetyl-2,5-dimethylthiophen-3-ylmethylthio)-5,5-dimethyl-2-isoxazolinedissolved in 50 ml of ethanol. The mixture was stirred for 5 hours underrefluxing, to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g(36.4%) of5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-2-ylmethylthio]-2-isoxazolineas a yellow oily substance.

¹H-NMR [CDC1₃/TMS, (ppm)]: 4.21 (2H, s), 3.95 (3H, s), 2.76 (2H, s),2.38 (3H, s), 2.34 (3H, s), 2.13 (3H, s), 1.42 (6H, s)

EXAMPLE 36 Production of5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylsulfonyl]-2-isoxazoline(present compound No. 2-0001)

0.61 g of m-chloroperbenzoic acid (purity: 70%, 3.5 mmoles) was added,with ice-cooling, to a solution of 0.4 g (1.2 mmoles) of5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylthio]-2-isoxazolinedissolved in 30 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 0.35 g (80%) of5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylsulfonyl]-2-isoxazolineas white crystals (melting point: 95.0 to 96.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.79 (2H, s), 3.95 (3H, s), 2.93 (2H, s),2.42 (3H, s), 2.37 (3H, s), 2.17 (3H, s), 1.47 (6H, s)

EXAMPLE 37 Production of5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylthio)-2-isoxazoline(present compound No. 7-0003)

0.26 g of sodium hydrosulfide (purity: 70%, 4.6 mmoles) was added to asolution of 0.3 g (1.6 mmoles) of5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 20 ml ofN,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto wereadded 0.22 g (1.6 mmoles) of anhydrous potassium carbonate and 0.25 g(1.6 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours.Thereto was added, with ice-cooling, 0.3 g (1.3 mmoles) of3-bromomethyl-4-trifluoromethyl-pyridine. The resulting mixture wasstirred at room temperature for 2 hours to give rise to a reaction.After confirmation of the completion of the reaction, the reactionmixture was poured into water, followed by extraction with ethylacetate. The resulting organic layer was washed with water and anaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (developing solvent: hexane-ethyl acetatemixed solvent) to obtain 0.45 g (yield: 98.9%) of5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylthio)-2isoxazolineas a yellow oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.98 (1H, s), 8.70 (1H, d), 7.51 (1H, d),4.47 (2H, s), 2.79 (2H, s), 1.43 (6H, s)

EXAMPLE 38 Production of5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfonyl)-2-isoxazoline(present compound No. 7-0001) and5,5-dimethyl-3-(4-trifluoromethyl-pyridine-N-oxide-3-ylmethylsulfonyl)-2-isoxazoline(present compound No. 7-0002)

0.77 g of m-chloroperbenzoic acid (purity: 70%, 4.5 mmoles) was added,with ice-cooling, to a solution of 0.45 g (1.6 mmoles) of5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylthio)-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 0.06 g (yield: 12.0%) of5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfonyl)-2-isoxazolineas light yellow crystals (melting point: 77.0 to 80.0° C.) and 0.12 g(yield: 23.1%) of5,5-dimethyl-3-(4-trifluoromethyl-pyridin-N-oxide-3-ylmethylsulfonyl)-2-isoxazolineas white crystals (melting point: 114.0 to 116.0° C.).

5,5-Dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfonyl)-2-isoxazoline

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.98 (1H, s), 8.84 (1H, d), 7.64 (1H, d),4.92 (2H, s), 3.09 (2H, s), 1.52 (6H, s)

5,5-Dimethyl-3-(4-trifluoromethyl-pyridin-N-oxide-3ylmethylsulfonyl)-2-isoxazoline

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.50 (1H, s), 8.25 (1H, d), 7.59 (1H, d),4.81 (2H, s), 3.12 (2H, s), 1.53 (6H, s)

EXAMPLE 39 Production of5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylthio]-2-isoxazoline(present compound No. 8-0002)

0.32 g of sodium hydrosulfide (purity: 70%, 4.00 mmoles) was added, atroom temperature, to a solution of 0.35 g (2.00 mmoles) of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 10 ml ofdimethylformamide. The mixture was stirred for 2 hours. To the reactionmixture were added 0.28 g (2.00 mmoles) of anhydrous potassiumcarbonate, 0.31 g (2.00 mmoles) of Rongalit and 0.45 g (2.00 mmoles) of5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine. The resultingmixture was stirred at room temperature for 2 hours to give rise to areaction. After confirmation of the completion of the reaction, thereaction mixture was poured into water, followed by extraction withethyl acetate. The resulting organic layer was washed with water and anaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography to obtain 0.55 g (yield: 85.9%) of5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylthio]-2-isoxazoline.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.81 (1H, s), 4.44 (2H, d), 4.12 (3H, s),2.81 (2H, s), 1.45 (6H, s)

EXAMPLE 40 Production of5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylsulfonyl]-2-isoxazoline(present compound No. 8-0001)

1.05 g of m-chloroperbenzoic acid (purity: 70%, 4.28 mmoles) was added,with ice-cooling, to a solution of 0.55 g (1.71 mmoles) of5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylthio]-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 4 hours to give rise to a reaction. Afterthe completion of the reaction, the reaction mixture was poured intowater, followed by extraction with chloroform. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, anaqueous sodium hydrogencarbonate solution and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The residue was purified by silica gelcolumn chromatography to obtain 0.45 g (yield: 75.0%) of5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylsulfonyl]-2-isoxazolineas white feather-like crystals (melting point: 175 to 176° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.89 (1H, s), 5.00 (2H, d), 4.11 (3H, s),3.11 (2H, s), 1.53 (6H, s)

EXAMPLE 41 Production of3-(5,5-dimethyl-2-isoxazolin-3-ylthiomethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine(present compound No. 3-0033)

A solution of 0.82 g (2.3 mmoles) of3-[5-chloro-1-(3-hydroxypropyl)-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio]-5,5-dimethyl-2-isoxazoledissolved in 5 ml of N,N-dimethylformamide was dropwise added to asuspension of 0.11 g (2.8 mmoles) of sodium hydride in 15 ml ofN,N-dimethylformamide. After the completion of the dropwise addition,the resulting mixture was stirred at room temperature for 30 minutes,then heated to 100° C., and stirred for 1 hour to give rise to areaction. After confirmation of the completion of the reaction, thereaction mixture was poured into water, followed by extraction withethyl acetate. The resulting organic layer was washed with an aqueouscitric acid solution and an aqueous sodium chloride solution, and thendried over magnesium sulfate. The resulting solution was subjected tovacuum distillation to obtain 0.77 g (yield: 100%) of3-(5,5-dimethyl-2-isoxazolin-3-ylthiomethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.37 (2H, t), 4.19 (2H, t), 4.15 (2H, s),2.80 (2H, s), 2.31 (2H, m), 1.42 (6H, s)

EXAMPLE 42 Production of3-(5,5-dimethyl-2-isoxazolin-3-ylsulfonylmethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine(present compound No. 3-0019)

1.25 g of m-chloroperbenzoic acid (purity: 70%, 5.1 mmoles) was added,with ice-cooling, to a solution of 0.77 g (2.3 mmoles) of3-(6,7-dihydro-3-trifluoromethyl-5H-pyrazolo[5,1-b][1,3]oxazin-4yl-methylthio)-5,5-dimethyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred for 1 hour andthen at room temperature for 12 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, an aqueous sodium hydrogencarbonate solution, water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography to obtain 0.36 g(yield: 43%) of3-(5,5-dimethyl-2-isoxazolin-3-ylsulfonylmethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazineas a white powder (melting point: 151.0 to 152.0° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.47 (2H, s), 4.40 (2H, t), 4.23 (2H, t),3.09 (2H, s), 2.34 (2H, m), 1.50 (6H, s)

Compound numbers shown in Tables 11 to 20 are referred to in theExamples.

TABLE 11

Melting point(° C.) or Com- refractive pound index No. R¹ R² R³ R⁴ n R⁵R⁶ Z₁ R²² R²³ R²⁴ (n_(D) ²⁰) 1-0001 Me Me H H 2 H H S Me H H 66–681-0002 Me Me H H 2 H H S Cl Me H 87–88 1-0003 Me Me H H 2 H H S H H Me95–97 1-0004 Me Me H H 2 H H S Cl H H 70–72 1-0005 Me Me H H 2 H H S H HCl 118–119 1-0006 Me Me H H 2 H H O H H H Impossible to measure 1-0007Me Me H H 2 H H O H H C(=O)OMe 124–125

TABLE 12

Melting point(° C.) Com- or pound refractive index No. R¹ R² R³ R⁴ n R⁵R⁶ Z² R²⁵ R²⁶ R²⁷ (n_(D) ²⁰) 2-0001 Me Me H H 2 H H S Me C(=NOMe)Me Me95–96 2-0002 Me Me H H 0 H H S Me C(=NOMe)Me Me 2-0003 Me Me H H 2 H H SH H H  99–101 2-0004 Me Me H H 2 H H S H Ome H 96–97 2-0005 Me Me H H 2H H S Cl H Cl 125–127 2-0006 Me Me H H 2 H H S Cl Cl Cl 158–160 2-0007Me Me H H 2 H H S Me Me Me 117–117 2-0008 Me Me H H 2 H H S Me C(=O)MeMe 146–148 2-0009 Me Me H H 2 H H S Ph C(=O)Me Me 1.5730 2-0010 Me Me HH 2 H H S Ph C(=NOMe)Me Me 129–131 2-0011 Me Me H H 2 H H S Cl C(=O)OmeCl 157–158 2-0012 Me Me H H 2 H H S Cl C(=O)NHMe Cl 178–180 2-0013 Me MeH H 2 H H O H H H 58–61 2-0014 Me Me H H 2 H H O Me H Cl 180–181

TABLE 13

Melting point(° C.) or Com- refractive pound index No. R¹ R² R³ R⁴ n R⁵R⁶ R²⁹ R²⁸ R³⁰ (n_(D) ²⁰) 3-0001 Me Me H H 0 H H CF₃ Ph Cl 89–90 3-0002Me Me H H 2 H H CF₃ Ph Cl 132–133 3-0003 Me Me H H 1 H H Ph Me ClImpossible to measure 3-0004 Me Me H H 2 H H CF₃ Ph SO₂Et 158–160 3-0005Me Me H H 2 H H CF₃ Ph N(Me)₂ 150–151 3-0006 Me Me H H 0 H H CF₃ Bu-t Cl79-81 3-0007 Me Me H H 0 H H CF₃ H Cl 120–122 3-0008 Me Me H H 0 H H CF₃CHF₂ Cl 41-42 3-0009 Me Me H H 0 H H Cl CHF₂ CF₃ 89–90 3-0010 Me Me H H2 H H CF₃ CHF₂ Cl 126–127 3-0011 Me Me H H 2 H H Cl CHF₂ CF₃ 136–1373-0012 Me Me H H 2 H H OEt Me CF₃ 124–125 3-0013 Me Me H H 2 H H CF₃ MeOMe 113–114 3-0014 Me Me H H 2 H H CF₃ Me O(2-Cl)Ph 67–70 3-0015 Me Me HH 2 H H CF₃ Me OPen-c 113–114 3-0016 Me Me H H 2 H H CF₃ Me CN 105–1083-0017 Me Me H H 2 H H Cl Et Cl 105–107 3-0018 Me Me H H 2 H H CHF₂ MeCl 78–79 3-0019 Me Me H H 2 H H CF₃ —(CH₂)₃O— 151–152 3-0020 Me Me H H 0H H CHF₂ Me Cl 1.5183 3-0021 Me Me H H 0 H H CF₃ Ph F 3-0022 Me Me H H 0H H CF₃ Ph SEt 3-0023 Me Me H H 0 H H CF₃ Ph N(Me)₂ 3-0024 Me Me H H 0 HH OMe Me CF₃ 3-0025 Me Me H H 0 H H OH Me CF₃ 3-0026 Me Me H H 0 H H OEtMe CF₃ 3-0027 Me Me H H 0 H H CF₃ Me F 3-0028 Me Me H H 0 H H CF₃ Me OMe3-0029 Me Me H H 0 H H CF₃ Me O(2-Cl)Ph 3-0030 Me Me H H 0 H H CF₃ MeOPen-c 3-0031 Me Me H H 0 H H CF₃ Me CN 3-0032 Me Me H H 0 H H Cl Et Cl3-0033 Me Me H H 0 H H CF₃ —(CH₂)₃O— 3-0034 Me Me H H 2 H H CF₃ H Cl138–140 3-0035 Me Me H H 2 H H H Me Cl 105–106 3-0036 Me Me H H 2 H H MeMe Me 148–150 3-0037 Me Me H H 2 H H Me Me Cl  99–101 3-0038 Me Me H H 2H H Cl Me Cl 143–145 3-0039 Me Me H H 2 H H CF₃ Me Cl 115–116 3-0040 MeMe H H 2 H H Cl Me CF₃ 120–122 3-0041 Me Me H H 2 H H CF₃ Me F 79–823-0042 Me Me H H 2 H H CF₃ Me OH 90–92 3-0043 Me Me H H 2 H H OMe Me CF₃125–126 3-0044 Me Me H H 2 H H CF₃ Me OEt 92–94 3-0045 Me Me H H 2 H HCF₃ Me OPr-i 69–71 3-0046 Me Me H H 2 H H CF₃ Me OPr 82–83 3-0047 Me MeH H 2 H H CF₃ Me OBu-t 86–89 3-0048 Me Me H H 2 H H CF₃ Me OBu 61–623-0049 Me Me H H 2 H H CF₃ Me OHex-c 124–125 3-0050 Me Me H H 2 H H CF₃Me OCH₂Pr-c 93–94 3-0051 Me Me H H 2 H H CF₃ Me OCH₂Pen-c 112–113 3-0052Me Me H H 2 H H CF₃ Me OCH₂Hex-c 56–59 3-0053 Me Me H H 2 H H CF₃ MeOCH₂C≡CH 92–93 3-0054 Me Me H H 2 H H CF₃ Me OCHF₂ 129–130 3-0055 Me MeH H 2 H H OCHF₂ Me CF₃ Impossible to measure 3-0056 Me Me H H 2 H H CF₃Me OCH₂CHF₂ 89–91 3-0057 Me Me H H 2 H H CF₃ Me OCH₂CF₃ 93–95 3-0058 MeMe H H 2 H H CF₃ Me OCH₂CN 1.4872 3-0059 Me Me H H 2 H H CF₃ Me OCH₂Ph79–81 3-0060 Me Me H H 2 H H CF₃ Me OPh 122–123 3-0061 Me Me H H 2 H HCF₃ Me O(3-Cl)Ph Impossible to measure 3-0062 Me Me H H 2 H H CF₃ MeO(3-OMe)Ph 1.5059 3-0063 Me Me H H 2 H H CF₃ Me O(4-Cl)Ph 68–69 3-0064Me Me H H 2 H H CF₃ Me O(4-Me)Ph 132–133 3-0065 Me Me H H 2 H H CF₃ MeO(4-OMe)Ph 115–117 3-0066 Me Me H H 2 H H CF₃ Me OC(═O)Me 130–131 3-0067Me Me H H 2 H H CF₃ Me SO₂Me 168–169 3-0068 Me Me H H 2 H H CF₃ Me SEt100–102 3-0069 Me Me H H 2 H H CF₃ Me SO₂Et 107–108 3-0070 Me Me H H 2 HH CF₃ Me SO₂Ph 166–168 3-0071 Me Me H H 2 H H CF₃ Me Me 105–107 3-0072Me Me H H 2 H H Ph Me Cl 127–129 3-0073 Me Me H H 2 H H CF₃ Et Cl111–112 3-0074 Me Me H H 2 H H Cl Et CF₃ 112–114 3-0075 Me Me H H 2 H HCF₃ Pr-i Cl 157–158 3-0076 Me Me H H 2 H H Cl Pr-i CF₃ 135–136 3-0077 MeMe H H 2 H H CF₃ Pr Cl 89–90 3-0078 Me Me H H 2 H H Cl Pr CF₃ 111–1133-0079 Me Me H H 2 H H CF₃ Bu-t H 101–103 3-0080 Me Me H H 2 H H CF₃Bu-t Cl 118–119 3-0081 Me Me H H 2 H H CF₃ Bu-s Cl 110–112 3-0082 Me MeH H 2 H H Cl Bu-s CF₃ 110–111 3-0083 Me Me H H 2 H H CF₃ Bu-i Cl 96–983-0084 Me Me H H 2 H H Cl Bu-i CF₃ 140–141 3-0085 Me Me H H 2 H H CF₃ BuCl 89–90 3-0086 Me Me H H 2 H H Cl Bu CF₃ 108–110 3-0087 Me Me H H 2 H HCF₃ CH₂Ph Cl 132–133 3-0088 Me Me H H 2 H H Cl CH₂Ph CF₃ 118–120 3-0089Me Me H H 2 H H CF₃ Pen-c Cl 130–131 3-0090 Me Me H H 2 H H Cl Pen-c CF₃147–148 3-0091 Me Me H H 2 H H CF₃ Hex-c Cl 151–152 3-0092 Me Me H H 2 HH CF₃ CH₂Pr-c Cl 93–95 3-0093 Me Me H H 2 H H Cl CH₂Pr-c CF₃ 129–1303-0094 Me Me H H 2 H H CF₃ 1-cyclopropylethyl Cl 87–89 3-0095 Me Me H H2 H H Cl 1-cyclopropylethyl CF₃ 121–123 3-0096 Me Me H H 2 H H CF₃CH₂(2-Methylcyclopropyl) Cl 102–103 3-0097 Me Me H H 2 H H ClCH₂(2-Methylcyclopropyl) CF₃ 118–119 3-0098 Me Me H H 2 H H CF₃ CH₂Bu-cCl 94–96 3-0099 Me Me H H 2 H H Cl CH₂Bu-c CF₃ 141–142 3-0100 Me Me H H2 H H CF₃ CH₂Pen-c Cl 127–129 3-0101 Me Me H H 2 H H Cl CH₂Pen-c CF₃146–149 3-0102 Me Me H H 2 H H CF₃ CH₂Hex-c Cl 152–154 3-0103 Me Me H H2 H H Cl CH₂Hex-c CF₃ 115–117 3-0104 Me Me H H 2 H H CF₃ CH₂CH═CH₂ Cl78–80 3-0105 Me Me H H 2 H H Cl CH₂CH═CH₂ CF₃ 105–106 3-0106 Me Me H H 2H H CF₃ CH₂C≡CH Cl 73–74 3-0107 Me Me H H 2 H H Cl CH₂C≡CH CF₃ 108–1093-0108 Me Me H H 2 H H CF₃ CHMeC≡CH Cl 95–96 3-0109 Me Me H H 2 H H ClCHMeC≡CH CF₃ 116–118 3-0110 Me Me H H 2 H H CF₃ CH₂C≡CMe Cl 114–1153-0111 Me Me H H 2 H H Cl CH₂C≡CMe CF₃ 115–116 3-0112 Me Me H H 2 H HCF₃ CHF₂ OMe 72–74 3-0113 Me Me H H 2 H H OMe CHF₂ CF₃ 108-109 3-0114 MeMe H H 2 H H CF₃ CH₂CHF₂ Cl  99–100 3-0115 Me Me H H 2 H H Cl CH₂CHF₂CF₃ 107–109 3-0116 Me Me H H 2 H H CF₃ CH₂CF₃ Cl 135–136 3-0117 Me Me HH 2 H H Cl CH₂CF₃ CF₃ 112–115 3-0118 Me Me H H 2 H H CF₃ CH₂OMe Cl 87–893-0119 Me Me H H 2 H H Cl CH₂OMe CF₃ 125–128 3-0120 Me Me H H 2 H H CF₃CH₂OEt Cl 97–98 3-0121 Me Me H H 2 H H Cl CH₂OEt CF₃ 128–129 3-0122 MeMe H H 2 H H CF₃ CH₂CH₂OH Cl 79–81 3-0123 Me Me H H 2 H H Cl CH₂CH₂OHCF₃ 93–94 3-0124 Me Me H H 2 H H CF₃ CH₂CH₂OMe Cl 102–104 3-0125 Me Me HH 2 H H Cl CH₂CH₂OMe CF₃ 118–119 3-0126 Me Me H H 2 H H CF₃ CH₂CH₂OEt Cl56–59 3-0127 Me Me H H 2 H H Cl CH₂CH₂OEt CF₃ 118–119 3-0128 Me Me H H 2H H CF₃ CH₂SMe Cl 103–105 3-0129 Me Me H H 2 H H Cl CH₂SMe CF₃ 128–1293-0130 Me Me H H 2 H H CF₃ CH₂SO₂Me Cl 157–159 3-0131 Me Me H H 2 H H ClCH₂SO₂Me CF₃ 165–166 3-0132 Me Me H H 2 H H CF₃ CH₂CH₂SO₂Me Cl 155–1573-0133 Me Me H H 2 H H Cl CH₂CH₂SO₂Me CF₃ 166–168 3-0134 Me Me H H 2 H HCF₃ CH₂CN Cl 128–129 3-0135 Me Me H H 2 H H Cl CH₂CN CF₃ 117–118 3-0136Me Me H H 2 H H CF₃ CH₂C(═O)OEt Cl 127–129 3-0137 Me Me H H 2 H H ClCH₂C(═O)OEt CF₃ 143–145 3-0138 Me Me H H 2 H H CF₃ CH₂C(═O)NH₂ Cl173–174 3-0139 Me Me H H 2 H H Cl CH₂C(═O)NH₂ CF₃ 182–183 3-0140 Me Me HH 2 H H CF₃ CH₂C(═O)N(Me)₂ Cl 142–143 3-0141 Me Me H H 2 H H ClCH₂C(═O)N(Me)₂ CF₃ 181–182 3-0142 Me Me H H 2 H H CF₃ CH₂C(═O)Me Cl148–149 3-0143 Me Me H H 2 H H Cl CH₂C(═O)Me CF₃ 163–164 3-0144 Me Me HH 2 H H CF₃ CH₂CH₂C(=O)Me Cl 89–91 3-0145 Me Me H H 2 H H Me Ph Me140–141 3-0146 Me Me H H 2 H H Me Ph Cl 124–125 3-0147 Me Me H H 2 H HEt Ph Cl 112–113 3-0148 Me Me H H 2 H H Pr Ph Cl 122–123 3-0149 Me Me HH 2 H H Pr-i Ph Cl 116–117 3-0150 Me Me H H 2 H H Bu-t Ph Cl 100–1023-0151 Me Me H H 2 H H CF₃ Ph H 111–112 3-0152 Me Me H H 2 H H CF₃ Ph Me129–132 3-0153 Me Me H H 2 H H CF₃ Ph CF₃ 112–113 3-9154 Me Me H H 2 H HCF₃ Ph F 90–91 3-0155 Me Me H H 2 H H CF₃ Ph OMe 104–106 3-0156 Me Me HH 2 H H CF₃ Ph OEt 129–131 3-0157 Me Me H H 2 H H CF₃ Ph OPr-i 86–883-0158 Me Me H H 2 H H CF₃ Ph OPr 117–118 3-0159 Me Me H H 2 H H CF₃ PhOBu-t 105–108 3-0160 Me Me H H 2 H H CF₃ Ph OCHF₂ 90–92 3-0161 Me Me H H2 H H CF₃ Ph SO₂Me 167–168 3-0162 Me Me H H 2 H H CF₃ Ph CN 113–1153-0163 Me Me H H 2 H H CF₃ (2-Cl)Ph Cl 153–154 3-0164 Me Me H H 2 H HCF₃ (3-Cl)Ph Cl 106–107 3-0165 Me Me H H 2 H H CF₃ (4-Cl)Ph Cl 142–1433-0166 Me Me H H 2 H H CF₃ (4-F)Ph Cl 135–138 3-0167 Me Me H H 2 H H CF₃(4-OMe)Ph Cl 136–138 3-0168 Me Me H H 2 H H CF₃ (4-Me)Ph Cl 129–1303-0169 Me Me H H 2 H H CF₃ (4-NO₂)Ph Cl 145–147 3-0170 Me Me H H 2 H HCF₃ (4-CN)Ph Cl 91–93 3-0171 Me Me H H 2 H H CF₃ (4-C(═O)Me)Ph Cl133–135 3-0172 Me Me H H 2 H H CF₃ (4-C(═O)OMe)Ph Cl 121–124 3-0173 MeMe H H 2 H H CF₃ Pyrmidin-2-yl Cl 148–150 3-0174 Me Me H H 2 H H CF₃4,6-Dimethoxypyrmidin- Cl 117–118 2-yl 3-0175 Me Me H H 2 H H CF₃ SO₂MeCl 146–148 3-0176 Me Me H H 2 H H CF₃ SO₂Ph Cl 145–148 3-0177 Me Me H H2 H H CF₃ C(═O)Me Cl 130–131 3-0178 Me Me H H 2 H H CF₃ C(═O)Ph Cl114–117 3-0179 Me Me H H 2 H H CF₃ C(═O)OMe Cl 104–106 3-0180 Me Et H H2 H H CF₃ Me Cl 108–110 3-0181 Me Me H H 0 H H CHF₂ Me Cl 1.5183 3-0182Me Me H H 0 H H Ph Me Cl 76–77 3-0183 Me Me H H 0 H H CF₃ Bu-t OMe1.4831 3-0184 Me Me H H 0 H H CF₃ CH₂C(═O)NH₂ Cl 179–180 3-0185 Me Me HH 0 H H Me Ph Cl 58–60

TABLE 14

Melting point(° C.) or refractive index R² R³ R⁴ n R⁵ R⁶ Z³ R³¹ R³²(n_(D) ²⁰ ) Me H H 2 H H O CF₃ Me 135–136 Me H H 2 H H S Me Cl 113–114Me H H 0 H H O CF₃ Me Me H H 0 H H S Me Cl Me H H 2 H H O Me Me 178–179Me H H 2 H H O CF₃ OEt 89–91 Me H H 2 H H O Ph Me 81–83 Me H H 2 H H SMe OEt 109–111

TABLE 15

Melting point(° C.) Com- or pound refractive index No. R¹ R² R³ R⁴ n R⁵R⁶ Z⁴ R³³ R³⁴ (n_(D) ²⁰) 5-0001 Me Me H H 2 H H NMe Cl Me 114–115 5-0002Me Me H H 2 H H NMe Cl Et 107–108 5-0003 Me Me H H 2 H H NMe CF₃ H142–143 5-0004 Me Me H H 2 H H NCHF₂ —(CH₂)₄— 123–125 5-0005 Me Me H H 2H H NPh Oet Me 1.5397 5-0006 Me Me H H 2 H H NPh OCHF₂ Me 1.5339 5-0007Me Me H H 2 H H NPh CF₃ H  99–101 5-0008 Me Me H H 2 H H NPh OCH₂CH═CH₂Me 87–90 5-0009 Me Me H H 1 H H NPh OCH₂CH═CH₂ Me 1.5702

TABLE 16

Melting point(° C.) Com- or pound refractive index No. R¹ R² R³ R⁴ n R⁵R⁶ Z⁵ R³⁵ R³⁶ (n_(D) ²⁰) 6-0001 Me Me H H 2 H H NCHF₂ —(CH₂)₄—Impossible to measure 6-0002 Me Me H H 2 H H NPh H Oet 107–108 6-0003 MeMe H H 2 H H NPh H OCHF₂ 1.5383 6-0004 Me Me H H 2 H H O Me H 100–1026-0005 Me Me H H 0 H H NCHF₂ —(CH₂)₄— 1.5264

TABLE 17

Melting point(° C.) or Com- refractive pound index No. R¹ R² R³ R⁴ n R⁵R⁶ R³⁷ R³⁸ R³⁹ R⁴⁰ (n_(D) ²⁰) 7-0001 Me Me H H 2 H H H CF₃ H H — 77–807-0002 Me Me H H 2 H H H CF₃ H H N-oxide 114–116 7-0003 Me Me H H 0 H HH CF₃ H H — 7-0004 Me Me H H 2 H H H H H H — 130–131 7-0005 Me Me H H 2H H H H H H N-oxide 166–168 7-0006 Me Me H H 2 H H Cl Ph H H — 118–1207-0007 Me Me H H 2 H H OMe Ph H H — 105–106 7-0008 Me Me H H 2 H H Cl MeH H — 115–116 7-0009 Me Me H H 2 H H OMe Me H H — 134–135 7-0010 Me Me HH 2 H H Me Me H H N-oxide 198–199 7-0011 Me Me H H 2 H H Ph Ph H H —161–162 7-0012 Me Me H H 1 H H H H H H — 97–99 7-0013 Me Me H H 0 H H(2-Chloropyridin- H H H — 154–155 3-yl)methylthio

TABLE 18

Melting point(° C.) or refractive index R¹ R² R³ R⁴ n R⁵ R⁶ R⁴¹ R⁴² R⁴³(n_(D) ²⁰) Me Me H H 2 H H H OMe CF₃ 175–176 Me Me H H 0 H H H OMe CF₃Me Me H H 2 H H H Cl Cl 119–120 Me Me H H 2 H H H OEt CF₃ 94–95 Me Me HH 2 H H H OMe OMe 186–187 Me Me H H 2 H H Me OMe CF₃ 143–144 Me Me H H 2H H OMe OMe CF₃ 144–145 Me Me H H 2 H H SMe OMe CF₃ 160–162 Me Me H H 2H H SO₂Me OMe CF₃ 144–146 Me Me H H 2 H H NH₂ OMe CF₃ 208–209 Me Me H H2 Pr-i H H H CF₃ 112–113 Me Me H H 0 Pr-i H H H CF₃ 1.4986

TABLE 19

Melting point(° C.) or Com- refractive pound index No. R¹ R² R³ R⁴ n R⁵R⁶ Y¹ (n_(D) ²⁰) 9-0001 Me Me H H 2 H H Pyridin-2-yl 116–118 9-0002 MeMe H H 2 H H Pyridin-2-yl 1-oxide 140–143 9-0003 Me Me H H 2 H HPyridin-4-yl 133–136 9-0004 Me Me H H 2 H H Pyridin-4-yl 1-oxide 110–1139-0005 Me Me H H 2 H H 1,2,4-Oxadiazol-3-yl Impossible to measure 9-0006Me Me H H 2 H H 3-Phenyl-1,2,4-oxadiazol-5-yl 153–454 9-0007 Me Me H H 2H H 3-Benzyl-1,2,4-oxadiazol-5-yl 108–109 9-0008 Me Me H H 2 H H2-Chlorothiazol-4-yl 110–112 9-0009 Me Me H H 2 H H1,4-Dimethylimidazol-5-yl 163–164 9-0010 Me Me H H 1 H H Pyridin-2-yl81–82 9-0011 Me Me H H 1 H H Pyridin-4-yl 94–96 9-0012 Me Me H H 1 H H1,4-Dimethylimidazol-5-yl 138–140 9-0013 Me Me H H 0 H H1,4-Dimethylimidazol-5-yl 1.5427

TABLE 20

Melting point(° C.) or Com- refractive pound index No. R¹ R² R³ R⁴ n R⁵R⁶ Y¹ (n_(D) ²⁰) 10-0001 Me Me H H 2 H H Benzimidazol-2-yl 171–17410-0002 Me Me H H 2 H H Benzothiophen-2-yl 181–183 10-0003 Me Me H H 2 HH 3-Chlorobenzothiophen-2-yl 109–112 10-0004 Me Me H H 2 H HBenzotriazol-1-yl 206–207 10-0005 Me Me H H 2 H H 1-Methylindazol-4-yl128–130 10-0006 Me Me H H 2 H H Benzothiazol-2-yl 142–143 10-0007 Me MeH H 2 H H Benzothiophen-3-yl 188–191 10-0008 Me Me H H 2 H H5-Chlorobenzothiophen-3-yl 129–130 10-0009 Me Me H H 2 H HBenzoxazol-2-yl 127–129 10-0010 Me Me H H 2 H H3-Methylbenzothiophen-2-yl 161–163 10-0011 Me Me H H 2 H H3-Bromobenzothiophen-2-yl 118–119 10-0012 Me Me H H 2 H HBenzofuran-2-yl 123–124 10-0013 Me Me H H 2 H H 2-Methylbenzofuran-7-yl135–137 10-0014 Me Me H H 2 H H 3-Bromobenzofuran-2-yl 107–108 10-0015Me Me H H 2 H H Benzothiophen-7-yl 95–97 10-0016 Me Me H H 2 H H1-Methylindazol-7-yl 89–90 10-0017 Me Me H H 2 H H3-Methylbenzofuran-2-yl 111–112 10-0018 Me Me H H 2 H H3-Chloro-1-methylindol-2-yl 162–165

PRODUCTION EXAMPLES OF INTERMEDIATES Reference Example 1 Production of3-chloro-5,5-7dimethyl-2-isoxazoline

534.0 g (4.0 moles) of N-chlorosuccinimide was gradually added, at 65 to70° C., to a solution of 182.7 g (2.05 moles) of glyoxylic acid aldoximedissolved in 2 liters of 1,2-dimethoxyethane. The mixture was refluxedfor 1 hour with heating. Thereto were added, with ice-cooling, 1,440.0 g(14.4 moles) of potassium hydrogencarbonate and 10 ml of water. Then,360.0 g (6.4 moles) of 2-methylpropene was added. The resulting mixturewas stirred at room temperature for 24 hours to give rise to a reaction.The reaction mixture was poured into water, followed by extraction withdiisopropyl ether. The resulting organic layer was washed with water andan aqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein, to obtain107.7 g (yield: 40.0%) of 3-chloro-5,5-dimethyl-2-isoxazoline as ayellow viscous liquid.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 2.93 (2H, s), 1.47 (6H, s)

Reference Example 2 Production of3-chloro-5-ethyl-5-methyl-2-isoxazoline

61.9 g (463.4 mmoles) of N-chlorosuccinimide was gradually added, at 60°C., to a solution of 20.6 g (231.7 mmoles) of glyoxylic acid aldoximedissolved in 500 ml of 1,2-dimethoxyethane. After the addition, themixture was refluxed for 10 minutes with heating. Thereto were added,with ice-cooling, 50 ml (463.4 mmoles) of 2-methyl-1-butene, 98.9 g(1,622 mmoles) of potassium hydrogencarbonate and 10 ml of water. Theresulting mixture was stirred for 12 hours to give rise to a reaction.The reaction mixture was poured into water, followed by extraction withn-hexane. The resulting organic layer was washed with water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum-distillation to remove the solvent contained therein, to obtain13.9 g (yield: 40.6%) of 3-chloro-5-ethyl-5-methyl-2-isoxazoline as ayellow viscous liquid.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 2.91 (2H, ABq, J=17.0, Δν=46.1 Hz), 1.73(2H, q) 1.42 (3H, s), 0.96 (3H, t)

Reference Example 3 Production of3-benzylthio-5,5-dimethyl-2-isoxazoline

3.2 g (23.2 mmoles) of anhydrous potassium carbonate and 3.0 g (22.5mmoles) of 3-chloro-5,5-dimethyl-2-isoxazoline were added, in a nitrogenatmosphere, to a solution of 2.8 g (22.5 mmoles) of benzylmercaptandissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at100° C. for 2 hours to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith water and an aqueous sodium chloride solution in this order andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography toobtain 3.1 g (yield: 62.0%) of 3-benzylthio-5,5-dimethyl-2-isoxazolineas a yellow oily substance (n_(D) ²⁰=1.5521).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.24-7.39 (5H, m), 4.26 (2H, s), 2.77 (2H,s), 1.40 (6H, s)

Reference Example 4 Production of3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline

4.6 g of m-chloroperbenzoic acid (purity: 70%, 18.8 mmoles) was added,with ice-cooling, to a solution of 4.1 g (15.0 mmoles) of3-(2,6-difluorobenzylthio)-5-ethyl-5-methyl-2-isoxazoline dissolved in50 ml of chloroform. The mixture was stirred for 1 hour and then at roomtemperature for 12 hours to give rise to a reaction. After thecompletion of the reaction the reaction mixture was poured into water,followed by extraction with chloroform. The resulting organic layer waswashed with an aqueous sodium hydrogensulfite solution, an aqueoussodium hydrogencarbonate solution, water and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The residue was purified by silica gelcolumn chromatography (developing solvent: hexane-ethyl acetate mixedsolvent) to obtain 1.5 g (yield: 34.8%) of3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline as a whitepowder (melting point: 30° C. or less).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.39-7.28 (1H, m), 7.03-6.94 (2H, m), 4.38(2H, s), 3.04 (1H, ABq, J=17.2, Δν=85.7 Hz), 3.12 (1H, s), 1.75 (2H, m),1.44 (3H, S)+1.41 (3H, s), 0.97 (3H, m)

Reference Example 5 Production of3-(2,6-difluorobenzylsulfonyl)-5-ethyl-5-methyl-2-isoxazoline

1.0 g of m-chloroperbenzoic acid (purity: 70%, 4.1 mmoles) was added,with ice-cooling, to a solution of 0.8 g (2.8 mmoles) of3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline dissolvedin 50 ml of chloroform. The mixture was stirred for 1 hour and then atroom temperature for 12 hours to give rise to a reaction. After thecompletion of the reaction the reaction mixture was poured into water,followed by extraction with chloroform. The resulting organic layer waswashed with an aqueous sodium hydrogensulfite solution, an aqueoussodium hydrogencarbonate solution, water and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The residue was purified by silica gelcolumn chromatography (developing solvent: hexane-ethyl acetate mixedsolvent) to obtain 0.6 g (yield: 75.0%) of3-(2,6-difluorobenzylsulfonyl)-5-ethyl-5-methyl-2-isoxazoline as a whitepowder (melting point: 64 to 65° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.36-7.46 (1H, m), 6.98-7.04 (2H, m), 4.73(2H, s) 3.04 (2H, ABq, J=17.2, Δν=51.1 Hz), 1.77 (2H, q) 1.46 (3H, s),0.97 (3H, t).

Reference Example 6 Production of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline

1.0 kg of an aqueous sodium methanethiolate solution (content: 15%, 2.14mmoles) was dropwise added, with ice-cooling, to a solution of 143.0 g(1.07 moles) of 3-chloro-5,5-dimethyl-2-isoxazoline dissolved in 500 mlof N,N-dimethylformamide. The mixture was stirred at room temperaturefor 12 hours to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 115.0 g(yield: 74.1%) of 5,5-dimethyl-3-methylthio-2-isoxazoline. This residue(741.2 mmoles) was dissolved in 1 liter of chloroform. Thereto wasadded, with ice-cooling, 392.0 g of m-chloroperbenzoic acid (purity:70%, 1.59 moles). The resulting mixture was stirred for 1 hour and thenat room temperature for 12 hours to give rise to a reaction. After thecompletion of the reaction, the separated m-chloroperbenzoic acid wasremoved by filtration. The resulting filtrate was washed with an aqueoussodium hydrogensulfite solution, water, an aqueous sodiumhydrogencarbonate solution and an aqueous sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was washed with diisopropyl etherto obtain 77.6 g (yield: 59.1%) of5,5-dimethyl-3-methylsulfonyl-2-isoxazoline as a white powder (meltingpoint: 82 to 84° C.).

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 3.26 (3H, s), 3.12 (2H, s), 1.51 (6H, s)

Reference Example 7 Production of 5,5-dimethyl-3-ethylthio-2-isoxazoline

1,500 ml of an aqueous solution containing 560.0 g (9.0 moles) of ethylmercaptan and 360.0 g (9.0 moles) of sodium hydroxide was added to asolution containing 3-chloro-5,5dimethyl-2-isoxazoline. The mixture wasstirred at 60 to 70° C. for 16 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with ethyl acetate. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein, to obtain 270.0 g of crude5,5-dimethyl-3-ethylthio-2-isoxazoline as a dark red oily substance.

Reference Example 8 Production of5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline

270.0 g (1.7 moles) of crude oily 5,5-dimethyl-3-ethylthio-2-isoxazolinewas dissolved in 1.0 liter of chloroform. Thereto was added, withice-cooling, 1,050 g of m-chloroperbenzoic acid (purity: 70%, 6.1moles). The resulting mixture was stirred for 1 hour and then at roomtemperature for 12 hours to give rise to a reaction. After confirmationof the completion of the reaction, the separated m-chloroperbenzoic acidwas removed by filtration. The resulting filtrate was washed with anaqueous sodium hydrogensulfite solution, an aqueous sodiumhydrogencarbonate solution, water and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The residue was washed with n-hexane toobtain 133.6 g (yield: 65.4%) of5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline as a white powder.

Reference Example 9 Production of1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol

20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentratedhydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) ofethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixturewas refluxed for 1 hour with heating, to give rise to a reaction. Afterthe completion of the reaction, the reaction mixture was subjected tovacuum distillation to remove the most part of the solvent containedtherein. The residue was mixed with water to precipitate crystals. Thecrystals were collected by filtration, washed with water until thefiltrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.68-7.41 (5H, m), 5.86 (1H, s), 3.71 (1H,s)

Reference Example 10

Production of5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

33.6 g (219.1 mmoles) of phosphorus oxychloride was added to 7.7 g(105.2 mmoles) of N,N-dimethylformamide with ice-cooling. Thereto wasadded, at room temperature, 20 g (87.7 mmoles) of1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol. The resulting mixture wasrefluxed for: 1 hour with heating, to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterwith ice-cooling, followed by extraction with chloroform. The resultingorganic layer was washed with an aqueous sodium hydrogencarbonatesolution and an aqueous sodium chloride solution in this order and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 19.1g (yield: 79.1%) of5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde as whitecrystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 10.06 (1H, s), 7.57 (5H, s)

Reference Example 11 Production of(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

A solution of 0.21 g (5.5 mmoles) of lithium aluminum hydride dissolvedin 70 ml of THF was cooled to -30° C. Thereto was gradually added asolution of 3 g (10.9 mmoles) of5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4carboaldehyde dissolvedin 30 ml of tetrahydrofuran. The resulting mixture was stirred at −30°C. for 30 minutes to give rise to a reaction. After the completion ofthe reaction, ethyl acetate was added, followed by stirring. Then, waterwas added, followed by stirring for a while. The reaction mixture wasfiltered under vacuum. The filtrate was extracted with ethyl acetate.The resulting organic layer was washed with an aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to vacuum distillation to remove the solventcontained therein, to obtain 3.0 g (yield: 99.9%) of(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol as whitecrystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.54-7.51 (5H, m), 4-71 (2H, d) 1.79 (1H,b)

Reference Example 12 Production of4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole

A solution of 3.0 g (10.9 mmoles) of(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolvedin 60 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g(3.8 mmoles) of phosphorus tribromide. The mixture was stirred at roomtemperature for 1 hour to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 3.6 g(yield: 95.8%) of4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole as whitecrystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.58-7.48 (5H, m), 4.48 (2H, s)

Reference Example 13 Production of5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

10.5 g (180.2 mmoles) of potassium fluoride was added to a solution of33.0 g (120.1 mmoles) of5-chloro1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolvedin 500 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for2 hours to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 26.5 g (yield: 85.0%) of5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.96 (1H, s), 7.68-7.51 (5H, m)

Reference Example 14 Production of(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

To a solution of 1.6 g (41.0 mmoles) of sodium borohydride dissolved in300 ml of methanol was added, with ice-cooling, a solution of 26.5 g(102.5 mmoles) of5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 200 ml of methanol. The resulting mixture was stirred at 0°C. for 30 minutes to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 28.5 g(yield: 100%) of(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.65-7.41-(5H, m), 4.68 (2H, d), 1.73 (1H,t)

Reference Example 15 Production of4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole

A solution of 27.5 g (105.7 mmoles) of(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolvedin 300 ml of diethyl ether was cooled to 0° C. Thereto was added 10.0 g(37.0 mmoles) of phosphorus tribromide. The mixture was stirred at roomtemperature for 2 hours to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water, followed byextraction with diethyl ether. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 30.3 g(yield: 88.8%) of4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.66-7.42 (5H, m), 4.44 (2H, s)

Reference Example 16 Production of1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol

373.8 g (3.0 moles) of tert-butylhydrazine hydrochloride and 50 ml ofconcentrated hydrochloric acid were added to a solution of 552.3 g (3.0moles) of ethyl trifluoroacetoacetate dissolved in 1,500 ml of ethanol.The mixture was refluxed for 2 days with heating, to give rise to areaction. After the completion of the reaction, the reaction mixture wassubjected to vacuum distillation to remove the most part of the solventcontained therein. The residue was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith water and an aqueous sodium chloride solution in this order andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was washed with n-hexane to obtain 369.0 g (yield:59.1%) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol as a whitepowder.

Reference Example 17

Production of1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

462.0 g (3.0 moles) of phosphorus oxychloride was added to 87.7 g (1.2moles) of N,N-dimethylformamide with ice-cooling. Thereto was added, atroom temperature, 208.2 g (1.0 moles) of1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol. The resulting mixturewas refluxed for 10 hours with heating, to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water, followed by extraction with chloroform. The resultingorganic layer was washed with water, a 5% aqueous sodium hydroxidesolution and water in this order and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (developing solvent: hexane-ethyl acetatemixed solvent) to obtain 131.5 g (yield: 21.7%) of1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde aswhite crystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.97 (1H, d), 1.76 (9H, s)

Reference Example 18 Production of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

A solution of 39.9 g (156.9 mmoles) of(1-tert-butyl-5chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 300 ml of methanol was cooled to 0° C. Thereto wasgradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixturewas stirred at room temperature for 3 hours to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water, followed by extraction with ethyl acetate. The resultingorganic layer was washed with an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 37.7 g (yield: 93.6%) of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.60 (2H, d), 1.72 (9H, s), 1.58 (1H, t)

Reference Example 19 Production of4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole

A solution of 9.2 g (35.7 mmoles) of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanoldissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto wasadded 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture wasstirred at room temperature overnight to give rise to a reaction. Afterthe completion of the reaction, the reaction mixture was poured intowater, followed by extraction with diethyl ether. The resulting organiclayer was washed with an aqueous sodium chloride solution and then driedover anhydrous magnesium sulfate. The resulting solution was subjectedto vacuum distillation to remove the solvent contained therein, toobtain 10.0 g (yield: 87.3%) of4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole.

Reference Example 20 Production of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol

43.5 g (136.1 mmoles) of4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole wasadded to a solution of 21.8 g of sodium hydrosulfide hydrate (purity:70%, 272.2 mmoles) dissolved in 300 ml of N,N-dimethylformamide. Themixture was stirred at room temperature overnight to give rise to areaction. After the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with diethyl ether. Theresulting organic layer was washed with an aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to vacuum distillation to remove the solventcontained therein, to obtain 32.3 g (yield: 87.0%) of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 3.65 (2H, d), 1.90 (1H, t), 1.70 (9H, s)

Reference Example 21 Production of1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole

15.0 g (108.4 mmoles) of anhydrous potassium carbonate and 19.3 g (135.5mmoles) of methyl iodide were added, at room temperature, to a solutionof 18.8 g (90.3 mmoles) of1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol dissolved in 100 ml ofN,N-dimethylformamide. The mixture was stirred for 15 hours to give riseto a reaction. After the completion of the reaction, the reactionmixture was poured into water, followed by extraction with diethylether. The resulting organic layer was washed with water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 20.0 g(yield: 99.8%) of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.

Reference Example 22 Production of1-tert-butyl-4-chloromethyl-5-methoxy-3-trifluoromethyl-1H-pyrazole

5.4 g of paraformaldehyde (180.2 mmoles in terms of formaldehyde) and 20ml of concentrated hydrochloric acid were added to a solution of 20.0 g(90.1 mmoles) of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazoledissolved in 90 ml of acetic acid. The mixture was stirred at 60° C. for30 minutes to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water, followed byextraction with diisopropyl ether. The resulting organic layer waswashed with water and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein, to obtain 21.7 g (yield: 89.0%) of1-tert-butyl-4-chloromethyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.

Reference Example 23 Production of3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole

10.0 g (72.3 mmoles) of anhydrous potassium carbonate and 12.8 g (90.3mmoles) of methyl iodide were added, at room temperature, to a solutionof 10.0 g (60.2 mmoles) of3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole dissolved in 50 ml ofN,N-dimethylformamide. The mixture was stirred for 15 hours to give riseto a reaction. After the completion of the reaction, the reactionmixture was poured into water, followed by extraction with diethylether. The resulting organic layer was washed with water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein, to obtain 9.8 g(yield: 90.7%) of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.

Reference Example 24 Production of4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole

0.45 g of paraformaldehyde (15.0 mmoles in terms of formaldehyde) and 5ml of concentrated hydrochloric acid were added to a solution of 1.00 g(5.6 mmoles) of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazoledissolved in 25 ml of acetic acid. The mixture was stirred at 80° C. for2 hours to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water and neutralizedwith potassium carbonate, followed by extraction with ethyl acetate. Theresulting organic layer was washed with water and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 0.83 g (yield: 65.0%) of4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.

Reference Example 25 Production of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

42.0 g (711.9 mmoles) of potassium fluoride was added to a solution of60.4 g (282.7 mmoles) of5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 700 ml of dimethyl sulfoxide. The mixture was stirred at120 to 140° C. for 5 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water, followed by extraction with ethyl acetate. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography (developing solvent: hexane-ethyl acetate mixed solvent)to obtain 36.8 g (yield: 66.0%) of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

Reference Example 26 Production of(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

To a solution of 3.9 g (102.6 mmoles) of sodium borohydride dissolved in500 ml of methanol was added, with ice-cooling, a solution of 36.8 g(187.6 mmoles) of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 200 ml of methanol. The resulting mixture was stirred at 0°C. for 30 minutes to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 35.4 g (yield: 95.4%) of(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

Reference Example 27 Production of4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole

A solution of 35.4 g (178.7 mmoles) of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-methanol dissolved in500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g(199.5 mmoles) of phosphorus tribromide. The mixture was stirred at roomtemperature for 12 hours to give rise to a reaction. After confirmationof the completion of the reaction, the reaction mixture was poured intowater, followed by extraction with diethyl ether. The resulting organiclayer was washed with water and an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 31.4 g (yield: 80.8%) of4-bromomethyl-5-fluoro1-methyl-3-trifluoromethyl-1H-pyrazole.

Reference Example 28 Production of (ethoxycarbonyl)malondialdehyde

12.6 g of sodium hydride (purity: 60%, 525.0 mmoles) was washed withdiethyl ether by decantation several times and then made into asolution; in 500 ml of diethyl ether. Thereto were added, in a nitrogencurrent at 0 to 10° C., 194 g (2.6 moles) of ethyl formate and 50 g(262.0 mmoles) of ethyl 3,3-diethoxy-propionate. The resulting mixturewas stirred at room temperature for 15 hours to give rise to a reaction.After confirmation of the completion of the reaction, the reactionmixture was poured into water, followed by washing with diethyl ether.The resulting aqueous layer was allowed to have a pH of 1 withhydrochloric acid, followed by extraction with dichloromethane. Theresulting organic layer was washed with an aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to vacuum distillation to remove the solventcontained therein, to obtain 37.6 g (yield: 100%) of crude(ethoxycarbonyl)malondialdehyde as a dark red oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.09 (2H, s), 5.26 (1H, s), 4.27 (2H, q),1.28 (3H, t)

Reference Example 29 Production of ethyl 1H-pyrazole-4-carboxylate

6.2 g (193 mmoles) of hydrazine was added, with ice-cooling, to asolution of 27.6 g (192 mmoles) of (ethoxycarbonyl)malondialdehydedissolved in 150 ml of ethanol. The mixture was stirred at roomtemperature for 17 hours to give rise to a reaction. The reactionmixture was subjected to vacuum distillation to remove the ethanolcontained therein. The residue was purified by silica gel columnchromatography (developing solvent: dichloromethane-ethyl acetate mixedsolvent) to obtain 19.4 g (72.4%) of ethyl 1H-pyrazole-4-carboxylate asyellow crystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.08 (2H, s), 5.30 (1H s), 4.31 (2H, q),1.36 (3H, t)

Reference Example 30 Production of ethyl1-ethyl-1H-pyrazole-4-carboxylate

3.7 g (26.8 mmoles) of anhydrous potassium carbonate and 4.2 g (26.6mmoles) of ethyl iodide were added to a solution of 1.5 g (10.7 mmoles)of ethyl 1H-pyrazole-4-carboxylate dissolved in 50 ml ofN,N-dimethylformamide. The mixture was stirred at room temperature for20hours to give rise to a reaction. After confirmation of the completionof the reaction, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The resulting organic layer was washedwith water and an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 1.6 g (yield: 88.9%) ofethyl 1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 7.90 (2H, s), 4.28 (2H, q), 4.18 (2H, q),1.51 (3H, t), 1.35 (3H, t)

Reference Example 31 Production of ethyl3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate

In a glass sealed tube were placed 1.6 g (9.5 mmoles) of ethyl1-ethyl-1H-pyrazole-4-carboxylate and 5.1 g (38.3 mmoles) ofN-chlorosuccinimide. There were allowed to react at 160° C. for 6 hours.After the completion of the reaction, the reaction mixture was cooled toroom temperature, washed with carbon tetrachloride and chloroform, andfiltered under vacuum. The resulting filtrate (organic layer) was washedwith water and an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 1.0 g (yield: 44.2%) ofethyl 3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate as a yellow oilysubstance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.36 (2H, q), 4.21 (2H, q), 1.44 (3H, t),1.38 (3H, t)

Reference Example 32 Production of(3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol

A solution of 0.16 g (4.2 mmoles) of lithium aluminum hydride dissolvedin 70 ml of tetrahydrofuran was cooled to −50° C. Thereto was graduallyadded dropwise a solution of 1.0 g (4.2 mmoles) of ethyl3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate dissolved in 30 ml oftetrahydrofuran. The mixture was stirred at −50° C. for 3 hours to giverise to a reaction. After confirmation of the completion of thereaction, ethyl acetate was added, followed by stirring for a while.Water was added, followed by stirring for a while. The resulting mixturewas filtered under vacuum. The filtrate was extracted with ethylacetate. The resulting organic layer was washed with water and anaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein, to obtain 0.82 g (yield: 100%) of(3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol as a brown oilysubstance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.52 (2H, s), 4.16 (2H, q), 1.43, (3H, t)

Reference Example 33 Production of4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole

A solution of 0.82 g (4.2 mmoles) of(3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol dissolved in 50 ml ofdiethyl ether was cooled to −30° C. Thereto was added 1.3 g (4.8 mmoles)of phosphorus tribromide. The mixture was stirred at room temperaturefor 12 hours to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 0.9 g (yield: 81.8%) of4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole as a yellow oilysubstance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.33 (2H, s), 4.13 (2H, q), 1.43 (3H, t)

Reference Example 34 Production of3-difluoromethyl-1-methyl-1H-pyrazol-5-ol

8.3 g (180.6 mmoles) of methylhydrazine and 5 ml of concentratedhydrochloric acid were added to a solution of 30.0 g (180.6 mmoles) ofethyl difluoroacetoacetate dissolved in 200 ml of ethanol. The mixturewas refluxed for 2 days with heating, to give rise to a reaction. Afterthe completion of the reaction, the reaction mixture was subjected tovacuum distillation to remove the most part of the solvent containedtherein. The residue was poured into water. The mixture was allowed tohave a pH of 4 using citric acid and extracted with ethyl acetate. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution in this order and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (developing solvent: hexane-ethyl acetatemixed solvent) to obtain 8.9 g (yield: 33.3) of3-difluoromethyl-1-methyl-1H-pyrazol-5-ol.

Reference Example 35 Production of5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde

41.6 g (270.1 mmoles) of phosphorus oxychloride was added, withice-cooling, to 7.9 g (108.0 mmoles) of N,N-dimethylformamide. Theretowas added, at room temperature, 8.0 g (54.0 mmoles) of3-difluoromethyl-1-methyl-1H-pyrazol-5-ol. The mixture was refluxed for4 hours with heating, to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water, followed byextraction with chloroform. The resulting organic layer was washed withwater, a 5% aqueous sodium hydroxide solution and water in this orderand then dried over anhydrous magnesium sulfate. The resulting solutionwas subjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 7.7 g(yield: 73.3%) of5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde as whitecrystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.96 (1H, s), 6.90 (1H, t, J=53.6 Hz), 3.93(3H, s)

Reference Example 36 Production of(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol

A solution of 7.2 g (37.0 mmoles) of5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde dissolvedin 100 ml of methanol was cooled to 0° C. Thereto was gradually added2.1 g (55.5 mmoles) of sodium borohydride. The mixture was stirred atroom temperature for 3 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein, to obtain3.8 g (yield: 52.1%) of(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 6.70 (1H, t, J=40.8 Hz), 4.63 (2H, s), 3.86(3H, s), 1.79 (1H, br)

Reference Example 37 Production of4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole

A solution of 2.0 g (10.0 mmoles) of(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol dissolvedin 50 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g(3.5 mmoles) of phosphorus tribromide. The mixture was stirred at roomtemperature overnight to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into ice water,followed by extraction with diethyl ether. The resulting organic layerwas washed with an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein, to obtain2.6 g (yield: 100.0%) of4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole.

Reference Example 38 Production of Trifluoroacetaldehyde Oxime Etherate

24.1 g (347.0 mmoles) of hydroxylamine hydrochloride and 160 ml of waterwere added to a solution of 50.0 g (347.0 mmoles) oftrifluoroacetaldehyde hemiethyl acetal dissolved in 80ml of methanol.Thereto was dropwise added, with ice-cooling, 80.0 g of a 50% aqueoussodium hydroxide solution (1.7 moles). After the completion of thedropwise addition, the resulting mixture was stirred at room temperaturefor 6 hours to give rise to a reaction. After the completion of thereaction, 10% hydrochloric acid was added for pH adjustment to 6. Theresulting mixture was extracted with diethyl ether. The extract wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was subjected to distillation to obtain 24.7 g(yield: 38.0%) of trifluoroacetaldehyde oxime etherate.

Reference Example 39 Production of Trifluoroacetohydroximoyl BromideEtherate

A solution of 38.8 g (218.0 mmoles) of N-bromosuccinimide dissolved in125 ml of N,N-dimethylformamide was added, with ice-cooling, to asolution of.24.7 g (131.7 mmoles) of trifluoroacetaldehyde oximeetherate dissolved in 50 ml of N,N-dimethylformamide. The mixture wasstirred at room temperature for 3 hours to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water, followed by extraction with diethyl ether. The resultingorganic layer was washed with an aqueous sodium chloride solution, andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was subjected to distillation to obtain 33.3 g(yield: 95.0%) of trifluoroacetohydroximoyl bromide etherate as a brownoily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.30 (1H, s)

Reference Example 40 Production of4-ethoxycarbonyl-5-methyl-3-trifluoromethylisoxazole

2.8 g (51.3 mmoles) of sodium methoxide was added to a solution of 6.7 g(51.3 mmoles) of ethyl acetoacetate dissolved in 80 ml of methanol.Thereto was added, with ice-cooling, a solution of 5.0 g (18.8 mmoles)of trifluorohydroximoyl bromide etherate dissolved in 20 ml of methanol.The resulting mixture was stirred at room temperature for 3 hours togive rise to a reaction. After the completion of the reaction, thereaction mixture was subjected to vacuum distillation to remove thesolvent contained therein. Water was added to the residue, followed byextraction with chloroform. The resulting organic layer was washed withan aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 2.9 g (yield: 69.0%) of4-ethoxycarbonyl-5-methyl-3-trifluoromethylisoxazole as a colorless oilysubstance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.36 (2H, q), 2;77 (3H,s), 1.37 (3H, t)

Reference Example 41 Production of(5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol

A solution of 0. 16 g (4.2 mmoles) of lithium aluminum hydride dissolvedin 15 ml of THF was cooled to 0° C. Thereto was gradually added asolution of 0.93 g (4.2 mmoles) of4-ethoxycarbonyl-5-methyl-3-trifluoromethylisoxazole dissolved in 15 mlof THF. The mixture was stirred at 0° C. for 1 hour to give rise to areaction. After the completion of the reaction, ethyl acetate was added,followed by stirring for a while. Water was added, followed by stirringfor a while. The reaction mixture was filtered under vacuum. Thefiltrate was extracted with diethyl ether. The resulting organic layerwas washed with an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein, to obtain0.5 g (yield: 60.0%) of(5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.60 (2H, d), 2.54 (3H, s), 1.66 (1H, br)

Reference Example 42 Production of4-bromomethyl-5-methyl-3-trifluoromethylisoxazole

A solution of 0.45 g (2.5 mmoles) of(5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol dissolved in 10 ml ofdiethyl ether was cooed to 0° C. Thereto was added 0.2 g (8.9 mmoles) ofphosphorus tribromide. The mixture was stirred at room temperature for 1hour to give rise to a reaction. After the completion of the reaction,the reaction mixture was poured into water, followed by extraction withdiethyl ether. The resulting organic layer was washed with an aqueoussodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein, to obtain 0.5 g (yield: 74.0%) of4-bromomethyl-5-methyl-3-trifluoromethylisoxazole.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.31 (2H, d), 2.51 (3H, s)

Reference Example 43 Production of(5-chloro-3-methyl-isothiazol-4-yl)-methanol

A solution of 2.06 g (10.0 mmoles) of ethyl5-chloro-3-methyl-isothiazole-4-carboxylate dissolved in 10 ml of THFwas dropwise added at −30° C., to. a solution of 0.42 g (11.0 mmoles) oflithium aluminum hydride dissolved in 10 ml of THF. The mixture wasstirred at the same temperature for 1 hour to give rise to a reaction.After confirmation of the completion of the reaction, ethyl acetate wasadded to the reaction mixture. The resulting mixture was poured intowater, followed by extraction with ethyl acetate. The resulting organiclayer was washed with water and an aqueous sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography to obtain 1.50 g (yield: 91.5%) of(5-chloro-3-methyl-isothiazol-4-yl)-methanol.

Reference Example 44 Production of4-chloromethyl-5-chloro-3-methylisothiazole

3.26 g (27.44 mmoles) of thionyl chloride was added, at roomtemperature, to a solution of 1.50 g (9.15 mmoles) of(5-chloro-3-methyl-isothiazol-4-yl)-methanol dissolved in 10 ml ofchloroform. The mixture was stirred for 3 hours to give rise to areaction. After confirmation of the completion of the reaction, thereaction mixture was subjected to vacuum distillation to remove thesolvent contained therein, to obtain 1.67 g (yield: quantitative) of4-chloromethyl-5-chloro-3-methylisothiazole.

Reference Example 45 Production of Methyl 4-trifluoromethylnicotinate

6.7 g (48.6 mmoles) of anhydrous potassium carbonate and 6.9 g (48.6mmoles) of methyl iodide were added to a solution of 4.6 g (24.1 mmoles)of 4-trifluoromethylnicotinic acid dissolved in 70 ml ofN,N-dimethylformamide. The mixture was stirred at room temperature for12 hours to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.77g (yield: 56.1%) of methyl 4-trifluoromethylnicotinate as a yellow oilysubstance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.11 (1H, s), 8.92 (1H, d), 7.64 (1H, d),3.99 (3H, s)

Reference Example 46 Production of (4trifluoromethylpyridin-3-yl)-methanol

A solution of 0.37 g (9.7 mmoles) of lithium aluminum hydride dissolvedin 100 ml of THF was cooled to −50° C. Thereto was gradually addeddropwise a solution of 2.0 g (9.8 mmoles) of methyl4-trifluoromethylnicotinate dissolved in 30 ml of THF. The mixture wasstirred at −50° C. for 3 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, ethyl acetate was added,followed by stirring for a while. Water was added, followed by stirringfor a while. The reaction mixture was filtered under vacuum. Thefiltrate was extracted with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g(yield: 35.3%) of (4-trifluoromethylpyridin-3-yl)-methanol as a yellowoily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.00 (1H, s), 8.73 (1H, d), 7.51 (1H, d),4.95 (2H, s)

Reference Example 47 Production of3-bromomethyl-4-trifluoromethylpyridine

A solution of 0.6 g (3.4. mmoles) of(4-trifluoromethylpyridin-3-yl)-methanol dissolved in 50 ml of diethylether was cooed to −30° C. Thereto was added 1.4 g (5.2 mmoles) ofphosphorus tribromide. The mixture was stirred at room temperature for12 hours to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 0.61 g (yield: 75.3%) of3-bromomethyl-4-trifluoromethylpyridine as a yellow oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.88 (1H, s), 8.73 (1H, d), 7.54 (1H, d),4.63 (2H, s)

Reference Example 48 Production of5-bromo-4-hydroxy-6-trifluoromethylpyrimidine

77.5 g (945.0 mmoles) of anhydrous sodium acetate was added, at roomtemperature, to a solution of 49.2 g (300.0 mmoles) of4-hydroxy-6-trifluoromethylpyrimidine dissolved in 600 ml of aceticacid. Thereto was gradually added 50.3 g (315 mmoles) of bromine at 45°C. The resulting mixture was stirred at the same temperature for 3 hoursto give rise to a reaction. After confirmation of the completion of thereaction, the reaction mixture was subjected to vacuum distillation toremove the solvent contained therein. The residue was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution in thisorder and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to vacuum distillation to remove the solventcontained therein. The residue was washed with n-hexane to obtain 38.9 g(yield: 53.4%) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine.

Reference Example 49 Production of5-bromo-4-chloro-6-trifluoromethylpyrimidine

24.3 g (100.0 mmoles) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidinewas suspended in 18.5 g (120.0 mmoles) of phosphorus oxychloride. Themixture was stirred at 100° C. for 2 hours to give rise to a reaction.After confirmation of the completion of the reaction, the reactionmixture was poured into water gradually, followed by extraction withchloroform. The resulting organic layer was washed with water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography to obtain 21.5 g(yield: 82.4%) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine.

Reference Example 50 Production of5-bromo-4-methoxy-6-trifluoromethylpyrimidine

16.7 ml of sodium methoxide (a 28% methanol solution, 86.4 mmoles) wasadded, at room temperature, to a solution of 21.5 g (82.2 mmoles) of5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 100 ml ofmethanol. The mixture was stirred to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was poured into water, followed by extraction withchloroform. The resulting organic layer was washed with water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas washed with n-hexane to obtain 19.2 g (yield: 91.0%) of5-bromo-4-methoxy-6-trifluoromethylpyrimidine.

Reference Example 51 Production of5-bromo-4-ethoxy-6-trifluoromethylpyrimidine

0.94 g (13.77 mmoles) of sodium ethoxide was added, at room temperature,to a solution of 3.00 g (11.48 mmoles) of5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 50 ml ofethanol. The mixture was stirred to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was poured into water, followed by extraction withchloroform. The resulting organic layer was washed with water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography to obtain 2.44 g(yield: 82.9%) of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine.

Reference Example 52 Production of4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde

30.0 ml of n-butyllithium (a 1.6 moles/liter n-hexane solution, 48.0mmoles) was gradually added, at −65 to −60° C., to a solution of 10.3 g(40.0 mmoles) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine dissolvedin 100 ml of tetrahydrofuran. The mixture was stirred for 30 minutes.Thereto was added 3.6 g (48.0 mmoles) of ethyl formate at the sametemperature. The resulting mixture was stirred at the same temperaturefor 3 hours to give rise to a reaction. The reaction mixture was pouredinto water, followed by extraction with ethyl acetate. The resultingorganic layer was washed with water and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to vacuum distillation to removethe solvent contained therein. The residue was purified by silica gelcolumn chromatography to obtain 1.3 g (yield: 15.8%) of4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 10.41 (1H, q), 8.91 (1H, s), 4.18 (3H, s)

Reference Example 53 Production of4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde

A solution of 5.76 g (21.3 mmoles) of5-bromo-4-ethoxy-6-trifluoromethylpyrimidine dissolved in 250 ml of THFwas cooled to −78° C. Thereto was dropwise added 22.6 ml ofn-butyllithium (a 1.6 moles/liter n-hexane solution, 36.1 mmoles). Themixture was stirred for 40 minutes. Thereto was added 2.7 g (45.1mmoles) of methyl formate. The resulting mixture was stirred for 1.5hours to give rise to a reaction. After the completion of the reaction,an aqueous ammonium chloride solution was added. The mixture wasextracted with diethyl ether. The resulting organic layer was washedwith an aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography (developing solvent:hexane-ethyl acetate mixed solvent) to obtain 3.82 g (yield:. 81.6%) of4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 10.41 (1H, s), 8.95 (1H, s), 4.63 (2H, q),1.48 (3H, t)

Reference Example 54 Production of(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

0.24 g (6.3 mmoles) of sodium borohydride was gradually added, at roomtemperature, to a solution of 1.3 g (6.3 mmoles) of4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 30 mlof methanol. The mixture was stirred for 3 hours to give rise to areaction. After confirmation of the completion of the reaction, thereaction mixture was poured into water, followed by extraction withethyl acetate. The resulting organic layer was washed with water and anaqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected tovacuum distillation to remove the solvent contained therein. The residuewas purified by silica gel column chromatography to obtain 0.42 g(yield: 32.1%) of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.93 (1H, s), 4.81 (2H, s), 4.13 (3H, s),2.26 (1H, br)

Reference Example 55 Production of(4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

A solution of 3.82 g (17.2 mmoles) of4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 50 mlof methanol was added, with ice-cooling, to a solution of 1.7 g (45.7mmoles) of sodium borohydride dissolved in 50 ml of methanol. Themixture was stirred at 0° C. for 1 hour to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water, followed by extraction with ethyl acetate. The resultingorganic layer was washed with an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein, to obtain 3.77 g (yield: 97.8%) of(4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.80 (1H, s), 4.81 (2H, s), 4.59 (2H, q),2.28 (1H, b), 1.48 (3H, t)

Reference Example 56 Production of5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine

1.19 g (10.1 mmoles) of thionyl chloride was added, at room temperature,to a solution of 0.42 g (2.02 mmoles) of(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol. The mixture wasstirred for 3 hours to give rise to a reaction. After confirmation ofthe completion of the reaction, the reaction mixture was subjected tovacuum distillation to remove the solvent contained therein, to obtain0.45 g (yield: quantitative) of5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine.

Reference Example 57 Production of5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine

A solution of 3.77 g (17.0 mmoles) of(4-ethoxy-6-trifluoromethylpyrimidine-5-yl)-methanol dissolved in 50 mlof diethyl ether was cooled to 0° C. Thereto was added 2.0 g (7.2mmoles) of phosphorus tribromide. The mixture was stirred at roomtemperature for 1 hour. The resulting salt was dissolved using methanol.The resulting mixture was stirred for 1 hour to give rise to a reaction.The reaction mixture was poured into water, followed by extraction withdiethyl ether. The resulting organic layer was washed with an aqueoussodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein, to obtain crude5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.79 (1H, s), 4.61 (2H, q), 4.55 (2H, s),1.49 (3H, t)

Reference Example 58 Production of(2-chloro-4-methylpyridin-3-yl)methanol

A solution of 1.9 g (10.0 mmoles) of methyl 2-chloro-4-methylnicotinatedissolved in 5.0 ml of THF was gradually added, at −65 to −60° C., to asuspension of 0.4 g (10.0 mmoles) of lithium aluminum hydride in 30 mlof tetrahydrofuran. The mixture was stirred for 30 minutes and at −20°C. for 1 hour to give rise to a reaction. The reaction mixture waspoured into water, followed by extraction with ethyl acetate. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution in this order and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to vacuum distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography to obtain 0.6 g (yield: 38.2%) of(2-chloro-4-methylpyridin-3-yl)methanol.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.19 (1H, d), 7.08 (1h, d), 4.85 (2H, s),2.49 (3H, s)

Reference Example 59 Production of3-acetyl-4-chloromethyl-2,5-dichlorothiophene

33 ml of titanium tetrachloride (a 2 moles/liter dichloromethanesolution, 66.0 mmoles) was dropwise added, at 10° C. with ice-cooling,to a solution of 5.0 g (32;4 mmoles) of 3-acetyl-2,5-dichlorothiophenedissolved in 26 ml (323.0 mmoles) of chloromethyl methyl ether. Themixture was stirred at room temperature for 2 hours to give rise to areaction. After the completion of the reaction, the reaction action.After the completion of the reaction, the reaction mixture was pouredinto ice water, followed by extraction with chloroform. The resultingorganic layer was washed with sodium bicarbonate, water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to vacuumdistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=9/1) to obtain 2.6 g (yield: 39.7%) of3-acetyl-4-chloromethyl-2,5-dichlorothiophene as yellow crystals.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.70 (2H, s), 2.56 (3H, s), 2.54 (3H, s),2.39 (3H, s)

Reference Example 60 Production of 3-bromo-2-bromomethylbenzofuran

2.7 g (15.3 mmoles) of N-bromosuccinimide and 0.4 g (2.7 mmoles) ofazobisisobutyronitrile were added to a solution of 2.8 g (13.3 mmoles)of 3-bromo-2-mehtylbenzofuran dissolved in 30 ml of monochlorobenzene.The mixture was stirred at 80° C. for 30 minutes to give rise to areaction. After confirmation of the disappearance of the raw materials,the reaction mixture was cooled to room temperature. The insolubles wereremoved by filtration. The filtrate was subjected to vacuum distillationto remove the solvent contained therein. The residue was poured intowater, followed by extraction with ethyl acetate. The resulting organiclayer was washed with water and an aqueous sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to vacuum distillation to remove thesolvent contained therein, to obtain 3.0 g (yield: 79.0%) of3-bromo-2-bromomethylbenzofuran.

Reference Example 61 Production of ethyl1-difluoromethyl-1H-pyrazole-4-carboxylate

6.0 g (43.5 mmoles) of anhydrous potassium carbonate was added to asolution of 3.0 g (21.4 mmoles) of ethyl 1H-pyrazole-4-carboxylatedissolved in 100 ml of N,N-dimethylformamide. Thereinto was blownchlorodifluoromethane. The resulting mixture was stirred at 130 to 140°C. for 3 hours to give rise to a reaction. After confirmation of thecompletion of the reaction, the reaction mixture was poured into water,followed by extraction with ethyl acetate. The resulting organic layerwas washed with water and an aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to vacuum distillation to remove the solvent containedtherein. The residue was purified by silica gel column chromatography(developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.67g (yield: 41.0%) of ethyl 1-difluoromethyl-1H-pyrazole-4-carboxylate asa colorless transparent oily substance.

¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.32 (1H, s), 8.04 (1H, s), 7.20 (1H, t),4.32 (2H, q), 1.37 (3H, t)

The herbicide of the present invention contains, as the activeingredient, an isoxazoline derivative represented by the genera formula[I] or a salt thereof.

In using the compound of the present invention as a herbicide, thepresent compound may be used by itself. It can also be used in the formof a powder, a wettable powder, an emulsifiable concentrate, a flowable,fine granules, granules, etc. by mixing with a carrier, a surfactant, adispersant, a adjuvant, etc. all generally used in formulation.

As the carrier used in formulation, there can be mentioned, for example,solid carriers such as talc, bentonite, clay, kaolin, diatomaceousearth, white carbon, vermiculite, calcium carbonate, slaked lime,siliceous sand, ammonium sulfate, urea and the like; and liquid carrierssuch as isopropyl alcohol, xylene, cyclohexane, methylnaphthalene andthe like.

As the surfactant and the dispersant, there can be mentioned, forexample, metal salts of alkylbenzenesulfonic acids, metal salts ofdinaphthylmethanedisulfonic acid, salts of alcohol sulfates,alkylarylsulfonic acid salts, ligninsulfonic acid salts, polyoxyethyleneglycol ether, polyoxyethylene alkyl aryl ethers, monoalkylates ofpolyoxyethylene sorbitan and the like. As the adjuvant, there can bementioned, for example, carboxymethyl cellulose, polyethylene glycol andgum arabic. The present herbicide, when used, is diluted to anappropriate concentration and sprayed or applied directly.

The herbicide of the present invention can be used by spraying onfoliage, application to soil, application on water surface, etc. Theamount of the active ingredient used is determined appropriately so asto meet the application purpose. The content of the active ingredient isappropriately determined according to the purpose. When the presentcompound is formulated as a powder or granules, the content is in arange of 0.01% to 10% by weight, preferably 0.05% to 5% by weight. Whenthe present compound is made into an emulsifiable concentrate or awettable powder, the amount is appropriately determined in a range of 1to 50% by weight, 5 to 30% by weight. When the present compound is madeinto a flowable, the amount is appropriately determined in a range of 1to 40% by weight, preferably 5 to 30% by weight.

The amount of the present herbicide used varies depending upon the kindof the compound used, the target weed, the tendency of weed emergence,the environmental conditions, the type of the herbicide used, etc. Whenthe present herbicide is used per se as in the case of a powder orgranules, the amount is appropriately selected in a range of 1 g to 50kg, preferably 10 g to 10 kg per 1 hectare in terms of the activeingredient. When the present herbicide is used in a liquid form as inthe case of an emulsifiable concentrate, a wettable powder or aflowable, the amount is appropriately selected in a range of 0.1 to50,000 ppm, preferably 10 to 10,000 ppm.

The compound of the present invention may be mixed as necessary with aninsecticide, a fungicide, other herbicide, a plant growth-regulatingagent, a fertilizer, etc.

Next, formulation from the present compound is described specifically byshowing typical examples of formulation. The kinds of compounds andadditives and their compounding ratios are not restricted to those shownbelow and can be varied widely. In the following description, “parts”refer to parts by weight.

<Formulation 1> Wettable Powder

10 parts of a compound (3-0006) were mixed with 0.5 part ofpolyoxyethylene octylphenyl ether, 0.5 part of a sodium salt of aβ-naphthalenesulfonic acid-formalin condensate, 20 parts of diatomaceousearth and 69 parts of clay. The mixture was mixed and pulverlized toobtain a wettable powder.

<Formulation 2> Flowable

20 parts of a coarsely ground compound (3-0006) were dispersed in 69parts of water. Thereto were added 4 parts of a polyoxyethylene styrylphenylether sulfate, 7 parts of ethylene glycol and 200 ppm, relative tothe herbicide produced, of Silicone AF-118N (a product of Asahi ChemicalIndustry, Co. Ltd.). The resulting mixture was stirred for 30 minutesusing a high-speed stirrer and then ground using a wet grinder to obtaina flowable.

<Formulation 3> Emulsion

To 30 parts of a compound (3-0006) were added 60 parts of an equalvolume mixture of xylene and isophorone and 10 parts of a surfactantmixture of a polyoxyethylene sorbitan alkylate, a polyoxyethylenealkylaryl polymer and an alkylaryl sulfonate. The resulting mixture wasstirred sufficiently to obtain an emulsifiable concentrate.

<Formulation 4> Granules

There were mixed 10 parts of a compound (3-0006), 80 parts of anextender which was a 1:3 mixture of talc and bentonite, 5 parts of whitecarbon and 5 parts of a surfactant mixture of a polyoxyethylene sorbitanalkylate, a polyoxyethylene alkylaryl polymer and an alkylarylsulfonate. To the mixture were added 10 parts of water. The resultingmixture was kneaded sufficiently to form a paste. The paste was extrudedthrough the eyes (diameter: 0.7 mm) of a sieve. The extrudate was driedand cut into a length of 0.5 to 1 mm to obtain granules.

Next, Application Examples of the present compound are described to showthe effect of the present compound.

Application Example 1 Test for Herbicidal Effect by Paddy Field SoilTreatment

A paddy field soil was filled in a plastic pot of 100 cm² and subjectedto puddling. Then, seeds of Echinochloa oryzicola Vasing and Monochoriavaginalis (Murm. f.) Presl var. plantaginea (Roxb.) Solms-Laub. weresowed and water was filled in a depth of 3 cm. Next day, wettablepowders produced in accordance with the Formulation 1 were diluted withwater and dropped on the water surface. The application amount of eachwettable powder was 1,000 g per 1 hectare in terms of the activeingredient. Then, breeding was made in a greenhouse, and the herbicidaleffect of each wettable powder was examined at the 21st day from thetreatment in accordance with the standard shown in Table 21. The resultsare shown in Table 22.

TABLE 21 Herbicidal effect (extent of growth inhibition) or Indexphytotoxicity 5 A herbicidal effect or phytotoxicity of 90% 4 Aherbicidal effect or phytotoxicity of 70% to less than 90% 3 Aherbicidal effect or phytotoxicity of 50% to less than 70% 2 Aherbicidal effect or phytotoxicity of 30% to less than 50% 1 Aherbicidal effect or phytotoxicity of 10% to less than 30% 0 Aherbicidal effect or phytotoxicity of 0% to less than 10%

TABLE 22 Monochoria vaginalis Echinochloa (Burm. F.) Presl var. Activeingredient oryzicola plantaginea (Roxb.) Compound No. (g/ha) VasingSolms-Laub.  1-0001 1000 5 5  1-0002 1000 5 5  1-0003 1000 5 5  1-00041000 5 5  1-0005 1000 5 5  2-0001 1000 5 5  2-0003 1000 5 5  2-0004 10005 5  2-0005 1000 5 5  2-0006 1000 5 5  2-0008 1000 5 5  2-0011 1000 5 5 2-0012 1000 5 5  3-0002 1000 5 5  3-0004 1000 5 5  3-0009 1000 5 5 3-0013 1000 5 5  3-0014 1000 5 5  3-0015 1000 5 5  3-0016 1000 5 5 3-0034 1000 5 5  3-0035 1000 5 5  3-0037 1000 5 5  3-0038 1000 5 5 3-0039 1000 5 5  3-0040 1000 5 5  3-0041 1000 5 5  3-0044 1000 5 5 3-0047 1000 5 5  3-0049 1000 5 5  3-0051 1000 5 5  3-0054 1000 5 5 3-0059 1000 5 5  3-0060 1000 5 5  3-0061 1000 5 5  3-0070 1000 5 5 3-0072 1000 5 5  3-0073 1000 5 5  3-0074 1000 5 5  3-0081 1000 5 5 3-0082 1000 5 5  3-0083 1000 5 5  3-0084 1000 5 5  3-0085 1000 5 5 3-0086 1000 5 5  3-0087 1000 5 5  3-0088 1000 5 5  3-0089 1000 5 5 3-0090 1000 5 5  3-0091 1000 5 5  3-0100 1000 5 5  3-0101 1000 5 5 3-0102 1000 5 5  3-0103 1000 5 5  3-0114 1000 5 5  3-0115 1000 5 5 3-0117 1000 5 5  3-0118 1000 5 5  3-0119 1000 5 5  3-0120 1000 5 5 3-0121 1000 5 5  3-0124 1000 5 5  3-0125 1000 5 5  3-0126 1000 5 5 3-0127 1000 5 5  3-0128 1000 5 5  3-0129 1000 5 5  3-0130 1000 5 5 3-0131 1000 5 5  3-0134 1000 5 5  3-0135 1000 5 5  3-0137 1000 5 5 3-0139 1000 5 5  3-0144 1000 5 5  3-0153 1000 5 5  3-0156 1000 5 5 3-0160 1000 5 5  3-0173 1000 5 5  3-0174 1000 5 5  3-0176 1000 5 5 3-0177 1000 5 5  3-0178 1000 5 5  3-0180 1000 5 5  4-0001 1000 5 5 4-0002 1000 5 5  4-0005 1000 5 5  4-0007 1000 5 5  4-0008 1000 5 5 5-0001 1000 5 5  5-0002 1000 5 5  5-0003 1000 5 5  5-0005 1000 5 5 5-0006 1000 5 5  5-0007 1000 5 5  6-0003 1000 5 5  6-0004 1000 5 5 7-0004 1000 5 5  7-0006 1000 5 5  7-0008 1000 5 5  7-0009 1000 5 5 8-0001 1000 5 5  8-0012 1000 5 5  9-0001 1000 5 5  9-0003 1000 5 5 9-0005 1000 5 5  9-0006 1000 5 5  9-0008 1000 5 5 10-0002 1000 5 410-0003 1000 5 5 10-0004 1000 5 5 10-0005 1000 5 5 10-0006 1000 5 510-0008 1000 5 5 10-0009 1000 5 5 10-0011 1000 5 5 10-0012 1000 5 510-0013 1000 5 5 10-0014 1000 5 5 10-0015 1000 5 5 10-0016 1000 5 510-0017 1000 5 5 10-0018 1000 5 5

Application Example 2 Test for Herbicidal Effect by Upland Field SoilTreatment

An upland field soil was filled in a plastic pot of 80 cm². Seeds ofEchinochloa crus-galli (L.) Beauv. var. crusgalli and Setaria viridis(L.) Beauv. were sowed, followed by covering with the same soil.Wettable powders produced in accordance with the Formulation 1 werediluted with water and sprayed uniformly on the soil surface using asmall sprayer, in an amount of 1,000 liters per 1 hectare so that theamount of each active ingredient became 1,000 g per 1 hectare. Then,breeding was made in a greenhouse, and the herbicidal effect of eachwettable powder was examined at the 21st day from the treatment inaccordance with the standard shown in Table 21. The results are shown inTable 23.

TABLE 23 Echinochloa curs-galli (L.) Active ingredient Beauv. Var.Setaria viridis Compound No. (g/ha) crus-galli (L.) Beauv.  1-0001 10005 5  1-0002 1000 5 5  1-0003 1000 5 5  1-0004 1000 5 5  1-0005 1000 5 5 1-0006 1000 5 4  2-0001 1000 5 5  2-0003 1000 5 5  2-0004 1000 5 5 2-0005 1000 5 5  2-0006 1000 5 4  2-0007 1000 4 4  2-0008 1000 5 5 2-0011 1000 5 4  2-0012 1000 5 5  3-0002 1000 5 5  3-0004 1000 5 5 3-0006 1000 4 4  3-0008 1000 5 5  3-0009 1000 5 5  3-0012 1000 5 5 3-0013 1000 5 5  3-0015 1000 5 5  3-0016 1000 5 5  3-0017 1000 5 5 3-0018 1000 5 5  3-0019 1000 5 5  3-0020 1000 5 5  3-0034 1000 5 5 3-0035 1000 5 5  3-0036 1000 5 5  3-0037 1000 5 5  3-0038 1000 5 5 3-0039 1000 5 5  3-0040 1000 5 5  3-0041 1000 5 5  3-0043 1000 5 5 3-0044 1000 5 5  3-0047 1000 5 5  3-0048 1000 5 5  3-0049 1000 5 5 3-0050 1000 5 5  3-0053 1000 5 5  3-0054 1000 5 5  3-0054 1000 5 5 3-0056 1000 5 5  3-0059 1000 5 5  3-0060 1000 5 5  3-0063 1000 5 5 3-0070 1000 4 4  3-0072 1000 5 5  3-0073 1000 5 5  3-0074 1000 5 5 3-0081 1000 5 5  3-0082 1000 5 5  3-0083 1000 5 5  3-0084 1000 5 5 3-0085 1000 5 5  3-0086 1000 5 5  3-0087 1000 5 5  3-0088 1000 5 4 3-0091 1000 5 5  3-0114 1000 5 5  3-0115 1000 5 5  3-0117 1000 5 5 3-0118 1000 5 5  3-0119 1000 5 5  3-0120 1000 5 5  3-0121 1000 5 5 3-0124 1000 5 5  3-0125 1000 5 5  3-0126 1000 5 5  3-0127 1000 5 5 3-0128 1000 5 5  3-0129 1000 5 5  3-0130 1000 5 5  3-0131 1000 5 5 3-0134 1000 5 5  3-0135 1000 5 5  3-0136 1000 5 5  3-0137 1000 5 5 3-0138 1000 4 5  3-0139 1000 5 5  3-0142 1000 5 5  3-0143 1000 5 5 3-0144 1000 5 5  3-0153 1000 5 5  3-0156 1000 5 5  3-0173 1000 5 5 3-0174 1000 5 5  3-0180 1000 5 5  4-0001 1000 5 5  4-0001 1000 4 3 4-0002 1000 5 5  4-0005 1000 5 5  4-0006 1000 5 5  4-0007 1000 5 5 4-0008 1000 5 5  5-0001 1000 5 5  5-0002 1000 5 5  5-0003 1000 5 5 5-0005 1000 5 4  5-0006 1000 5 5  5-0007 1000 5 5  6-0001 1000 5 5 6-0003 1000 5 5  6-0004 1000 5 5  7-0002 1000 5 5  7-0004 1000 5 4 7-0006 1000 5 5  7-0007 1000 5 4  7-0008 1000 5 5  7-0009 1000 5 5 8-0001 1000 5 5  8-0004 1000 5 5  8-0005 1000 5 4  8-0007 1000 5 5 9-0001 1000 5 5  9-0005 1000 5 4  9-0006 1000 5 4  9-0007 1000 4 4 9-0008 1000 5 5 10-0003 1000 5 5 10-0004 1000 5 5 10-0005 1000 5 510-0006 1000 5 4 10-0009 1000 5 5 10-0012 1000 5 4 10-0013 1000 5 510-0014 1000 5 5 10-0015 1000 5 5 10-0016 1000 5 4 10-0017 1000 5 510-0018 1000 5 5

Application Example 3 Test for Herbicidal Effect by Upland FoliageTreatment

A sand was filled in a plastic pot of 80 cm². Seeds of Echinochloacrus-galli (L.) Beauv. var. crus-galli and Setaria viridis (L.) Beauv.were sowed. Breeding was made in a greenhouse for 2 weeks. Wettablepowders produced in accordance with the Formulation 1 were diluted withwater and sprayed on the whole foliage of plants from above the plantsusing a small sprayer in an amount of 1,000 liters per 1 hectare so thatthe amount of each active ingredient became 1,000 g per 1 hectare. Then,breeding was made in the greenhouse, and the herbicidal effect of eachwettable powder was examined at the 14th day from the treatment inaccordance with the standard shown in Table 21. The results are shown inTable 24.

TABLE 24 Echinochloa curs-galli (L.) Active ingredient Beauv. Var.Setaria viridis Compound No. (g/ha) crus-galli (L.) Beauv. 1-0001 1000 54 1-0004 1000 5 4 2-0001 1000 5 4 2-0003 1000 5 4 2-0004 1000 5 4 2-00081000 5 5 2-0011 1000 5 4 3-0008 1000 4 4 3-0010 1000 5 4 3-0011 1000 5 43-0013 1000 5 5 3-0015 1000 5 4 3-0035 1000 4 4 3-0036 1000 4 4 3-00371000 5 4 3-0038 1000 5 5 3-0039 1000 5 5 3-0044 1000 5 4 3-0049 1000 4 43-0073 1000 5 4 3-0074 1000 5 4 3-0076 1000 5 4 3-0077 1000 5 4 3-00811000 4 4 3-0082 1000 4 4 3-0083 1000 4 4 3-0084 1000 4 4 3-0085 1000 4 43-0086 1000 4 4 3-0092 1000 4 4 3-0104 1000 5 4 3-0105 1000 5 4 3-01061000 5 4 3-0107 1000 5 5 3-0115 1000 5 4 3-0118 1000 5 4 3-0119 1000 5 43-0120 1000 5 5 3-0144 1000 5 5 4-0002 1000 5 4 4-0005 1000 5 4 5-00011000 5 4 5-0002 1000 5 5 5-0003 1000 5 4 5-0007 1000 5 5 6-0004 1000 5 47-0008 1000 5 5 7-0009 1000 4 4 8-0001 1000 5 4 9-0001 1000 4 4 9-00051000 4 4 9-0008 1000 4 4

INDUSTRIAL APPLICABILITY

The compound represented by the general formula [I] according to thepresent invention shows an excellent herbicidal effect over a wideperiod from before germination to growth, to various weeds causingproblems in upland fields, for example, broadleaf weeds [e.g. Polygonumlapathifolium L. subsp. nodosum (Pers.) Kitam., Amaranthus viridis L.,Chenopodium album L., Stellaria media (L.) Villars, Abutilon theophrastiMedik., Sida spinosa, Sesbaria exaltata, ipomoea spp. and Xanthiumstrumarium L.], perennial or annual cyperaceous weeds [e.g. Cyperusrotundus L., Cyperus esculentus, Kyllinga brevifolia Rottb. subsp.leiolepis (Fraxch. et Savat.) T. Koyama, Cyperus microiria Steud., andCyperus iria L.], and Gramineae weeds [e.g. Echinochloa crus-galli (L.)Beauv. var. crus-galli, Digitaria ciliaris (Retz.) Koeler, Setariaviridis (L.) Beauv., Poa annua L., Sorghum halepense (L.) Pers.,Alopecurus aequalis Sobol. var. amurensis (Komar.) Ohwi, and Avena fatuaL.]. Further, the present compound shows a herbicidal effect also toweeds emerging in paddy fields, i.e. annual weeds [e.g. Echinochloaoryzicola Vasing., Cyperus difformis L., Mohochoria vaginalis (Burm. f.)Presl. var. plantaginea (Roxb.) Solms-Laub., and Lindernia procumbens]and perennial weeds [e.g. Sagittaria trifolia L., Sagittaria pygmaeaMiq., Cyperus serotinus Rottb., Eleocharis kuroguwai Ohwi, and Scirpusjuncoides Roxb. subsp. hotarui (Ohwi) T. Koyama, Alisma canaliculatum].

The herbicide of the present invention has high safety to crops,particularly to rice, wheat, barley, corn, grain sorghum, soybean,cotton, sugar beat, etc.

1. An isoxazoline derivative represented by the following general formula [I] or a pharmaceutically acceptable salt thereof:

wherein R¹ and R² may be the same or different and are each a hydrogen atom, a C1 to C10 alkyl group, a C3 to C8 cycloalkyl group or a C3 to C8 cycloalkyl C1 to C3 alkyl group; or R¹ and R² may be bonded to each other to form a C3 to C7 spiro ring together with the carbon atoms to which they bond; R³ and R⁴ may be the same or different and are each a hydrogen atom, a C1 to C10 alkyl group or a C3 to C8 cycloalkyl group; or R³ and R⁴ may be bonded to each other to form a C3 to C7 spiro ring together with the carbon atoms to which they bond; or R¹, R², R³ and R⁴ may form a 5- to 8-membered ring together with the carbon atoms to which they bond; R⁵ and R⁶ may be the same or different and are each a hydrogen atom or a C1 to C10 alkyl group; Y is a 5- to 6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group having one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; the heterocyclic group may be substituted with 0 to 6 same or different groups selected from the following substituent group α; when the heterocyclic group is substituted at the two adjacent positions with two alkyl groups, two alkoxy groups, an alkyl group and an alkoxy group, an alkyl group and an alkylthio group, an alkyl group and an alkylsulfonyl group, an alkyl group and a monoalkylamino group, or an alkyl group and a dialkylamino group, all selected from the substituent group α, the two groups may form, together with the atoms to which they bond, a 5- to 8-membered ring which may be substituted with 1 to 4 halogen atoms; the hetero atom of the heterocyclic group, when it is a nitrogen atom, may be oxidized to become N-oxide; wherein n is an integer of 0 to 2; wherein Substituent group α is at least one member selected from the group consisting of: hydroxyl group; thiol group; halogen atoms; C1 to C10 alkyl groups; C1 to C10 alkyl groups each mono-substituted with a group selected from the following substituent group β, C1 to C4 haloalkyl groups; C3 to C8 cycloalkyl groups; C1 to C10 alkoxy groups; C1 to C10 alkoxy groups each mono-substituted with a group selected from the following substituent group γ; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylthio groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6 alkenyl groups; C2 to C6 alkenyloxy groups; C2 to C6 alkynyl groups; C2 to C6 alkynyloxy groups; C1 to C10 alkylsulfinyl groups; C1 to C10 alkylsulfinyl groups each mono-substituted with a group selected from the substituent group γ; C1 to C10 alkylsulfonyl groups; C1 to C10 alkylsulfonyl groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylsulfinyl groups; C1 to C10 alkylsulfonyloxy groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylsulfonyl groups; C1 to C10 alkylsulfonyloxy groups; C1 to C4 haloalkylsulfonyloxy groups; optionally substituted phenyl group; optionally substituted phenoxy group; optionally substituted phenylthio group; optionally substituted aromatic heterocyclic groups; optionally substituted aromatic heterocyclic oxy groups; optionally substituted aromatic heterocyclic thio groups; optionally substituted phenylsulfinyl groups; optionally substituted phenylsulfonyl groups; optionally substituted aromatic heterocyclic sulfonyl groups; optionally substituted phenylsulfonyloxy groups; acyl groups; C1 to C4 haloalkylcarbonyl groups; optionally substituted benzylcarbonyl group; optionally substituted benzoyl group; carboxyl group; C1 to C10 alkoxycarbonyl groups; optionally substituted benzyloxycarbonyl group; optionally substituted phenoxycarbonyl group; cyano group; carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group); C1 to C6 acyloxy groups; C1 to C4 haloalkylcarbonyloxy groups; optionally substituted benzylcarbonyloxy group; optionally substituted benzoyloxy group; nitro group; and amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl group, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group, and optionally substituted phenylsulfonyl group); wherein Substituent group β is at least one member selected from the group consisting of: hydroxyl group; C3 to C8 cycloalkyl groups (which may be substituted with halogen atom or alkyl group); C1 to C10 alkoxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylsulfonyl groups; C1 to C10 alkoxycarbonyl groups; C2 to C6 haloalkenyl groups; amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, C1 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups, C1 to C10 alkylsulfonyl groups and C1 to C4 haloalkylsulfonyl groups); carbamoyl group (its nitrogen atom may be substituted with same or different C1 to C10 alkyl groups); C1 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups; C1 to C10 alkoxyimino groups; cyano group; optionally substituted phenyl group; and optionally substituted phenoxy group; and wherein Substituent group γ is at least one member selected from the group consisting of: C1 to C10 alkoxycarbonyl groups; optionally substituted phenyl group; optionally substituted aromatic heterocyclic groups; cyano group; and carbamoyl group (its nitrogen atom may be substituted with same or different C1 to C10 alkyl groups).
 2. An isoxazoline derivative according to claim 1, wherein the substituent group α consists of hydroxyl group; halogen atoms; C1 to C10 alkyl groups; C1 to C10 alkyl groups each mono-substituted with a group selected from the substituent group β, C1 to C4 haloalkyl groups; C3 to C8 cycloalkyl groups; C1 to C10 alkoxy groups; C1 to C10 alkoxy groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylthio groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6 alkenyl groups; C2 to C6 alkenyloxy groups; C2 to C6 alkynyl groups; C2 to C6 alkynyloxy groups; C1 to C10 alkylsulfonyl groups; C1 to C4 haloalkylsulfonyl groups; optionally substituted phenyl group; optionally substituted phenoxy group; optionally substituted phenylthio group; optionally substituted aromatic heterocyclic groups; optionally substituted aromatic heterocyclic oxy groups; optionally substituted aromatic heterocyclic thio groups; optionally substituted phenylsulfonyl groups; optionally substituted aromatic heterocyclic sulfonyl groups; C1 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups; optionally substituted benzylcarbonyl group; optionally substituted benzoyl group; carboxyl group; C1 to C10 alkoxycarbonyl groups; cyano group; carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group); nitro group; and amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group, and optionally substituted phenylsulfonyl group); when the heterocyclic group is substituted at the two adjacent positions with two alkyl groups, two alkoxy groups, an alkyl group and an alkoxy group, an alkyl group and an alkylthio group, an alkyl group and an alkylsulfonyl group, an alkyl group and a monoalkylamino group, or an alkyl group and a dialkylamino group, all selected from the substituent group α, the two groups may form, together with the atoms to which they bond, a 5- to 8-membered ring which may be substituted with 1 to 4 halogen atoms.
 3. An isoxazoline derivative according to claim 2, wherein the substituent group α consists of halogen atoms; C1 to C10 alkyl groups; C1 to C4 haloalkyl groups; C1 to C10 alkoxy C1 to C3 alkyl groups; C3 to C8 cycloalkyl groups (which may be substituted with halogen atom or alkyl group); C1 to C10 alkoxy groups; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxy groups; optionally substituted phenoxy group; C1 to C10 alkylthio groups; C1 to C10 alkylsulfonyl groups; acyl groups; C1 to C4 haloalkylcarbonyl groups; C1 to C10 alkoxycarbonyl groups; cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different C1 to C10 alkyl groups).
 4. An isoxazoline derivative according to claim 1, wherein R¹ and R² are the same or different and are each a methyl group or an ethyl group; and R³, R⁴, R⁵ and R⁶ are each a hydrogen atom.
 5. An isoxazoline derivative according to claim 1, wherein Y is a 5- or 6-membered aromatic heterocyclic group having a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
 6. An isoxazoline derivative according to claim 5, wherein Y is a thienyl group, a pyrazolyl group, an isoxazolyl group, an isothiazolyl group, a pyridyl group or a pyrimidinyl group.
 7. An isoxazoline derivative according to claim 6, wherein Y is a thiophen-3-yl group, a pyrazol-4-yl group, a pyrazol-5-yl group, an isoxazol-4-yl group, an isothiazol-4-yl group, a pyridyn-3-yl group or a pyrimidin-5-yl group.
 8. An isoxazoline derivative according to claim 7, wherein Y is a thiophen-3-yl group and the thiophene ring is substituted with the substituent group α at the 2- and 4-positions.
 9. An isoxazoline derivative according to claim 7, wherein Y is a pyrazol-4-yl group and the pyrazole ring is substituted at the 3- and 5-positions with the substituent group α and at the 1-position with a hydrogen atom, a C1 to C10 alkyl group, a C1 to C10 alkyl group mono-substituted with a group selected from the substituent group β, a C1 to C4 haloalkyl group, a C3 to C8 cycloalkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, a C1 to C10 alkylsulfinyl group, a C1 to C10 alkylsulfonyl group, a C1 to C10 alkylsulfonyl group mono-substituted with a group selected from the substituent group γ, a C1 to C4 haloalkylsulfonyl group, an optionally substituted phenyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted phenylsulfonyl group, an optionally substituted aromatic heterocyclic sulfonyl group, an acyl group, a C1 to C4 haloalkylcarbonyl group, an optionally substituted benzylcarbonyl group, an optionally substituted benzoyl group, a C1 to C10 alkoxycarbonyl group, an optionally substituted benzyloxycarbonyl group, an optionally substituted phenoxycarbonyl group, a carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group), an amino group or an amino group having its nitrogen atom substituted with same or different groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group, acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group and optionally substituted phenylsulfonyl group.
 10. An isoxazoline derivative according to claim 7, wherein Y is a pyrazol-5-yl group and the pyrazole ring is substituted at the 4-position with the substituent group α and at the 1-position with a hydrogen atom, a C1 to C10 alkyl group, a C1 to C10 alkyl group mono-substituted with a group selected from the substituent group β, a C1 to C4 haloalkyl group, a C3 to C8 cycloalkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, a C1 to C10 alkylsulfinyl group, a C1 to C10 alkylsulfonyl group, a C1 to C10 alkylsulfonyl group mono-substituted with a group selected from the substituent group γ, a C1 to C4 haloalkylsulfonyl group, an optionally substituted phenyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted phenylsulfonyl group, an optionally substituted aromatic heterocyclic sulfonyl group, an acyl group, a C1 to C4 haloalkylcarbonyl group, an optionally substituted benzylcarbonyl group, an optionally substituted benzoyl group, a C1 to C10 alkoxycarbonyl group, an optionally substituted benzyloxycarbonyl group, an optionally substituted phenoxycarbonyl group, a carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group), or an amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group, acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group and optionally substituted phenylsulfonyl group).
 11. An isoxazoline derivative according to claim 7, wherein Y is an isoxazol-4-yl group and the isoxazole ring is substituted with the substituent group α at the 3- and 5-positions.
 12. An isoxazoline derivative according to claim 7, wherein Y is an isothiazol-4-yl group and the isothiazole ring is substituted with the substituent group α at the 3- and 5-positions.
 13. An isoxazoline derivative according to claim 7, wherein Y is a pyridin-3-yl group and the pyridine ring is substituted with the substituent group α at the 2- and 4-positions.
 14. An isoxazoline derivative according to claim 7, wherein Y is a pyrimidin-5-yl group and the pyrimidine ring is substituted with the substituent group α at the 4- and 6-positions.
 15. An isoxazoline derivative according to claim 1, wherein n is an integer of
 2. 16. An isoxazoline derivative according to claim 1, wherein n is an integer of
 1. 17. An isoxazoline derivative according to claim 1, wherein n is an integer of
 0. 18. A herbicide containing, as the active ingredient, an isoxazoline derivative set forth in claim 1 or a pharmaceutically acceptable salt thereof. 